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Biomaterial-based Platforms for Modulating Immune Components against Cancer and Cancer Stem Cells
Abstract
Immunotherapy involves the therapeutic alteration of the patient's immune system to identify, target, and eliminate cancer cells. Dendritic cells, macrophages, myeloid-derived suppressor cells, and regulatory T cells make up the tumor microenvironment. In cancer, these immune components (in association with some non-immune cell populations like cancer-associated fibroblasts) are directly altered at a cellular level. By dominating immune cells with molecular cross-talk, cancer cells can proliferate unchecked. Current clinical immunotherapy strategies are limited to conventional adoptive cell therapy or immune checkpoint blockade. Targeting and modulating key immune components presents an effective opportunity. Immunostimulatory drugs are a research hotspot, but their poor pharmacokinetics, low tumor accumulation, and non-specific systemic toxicity limit their use. This review describes the cutting-edge research undertaken in the field of nanotechnology and material science to develop biomaterials-based platforms as effective immunotherapeutics. Various biomaterial types (polymer-based, lipid-based, carbon-based, cell-derived, etc.) and functionalization methodologies for modulating tumor-associated immune/non-immune cells are explored. Additionally, emphasis has been laid on discussing how these platforms can be used against cancer stem cells, a fundamental contributor to chemoresistance, tumor relapse/metastasis, and failure of immunotherapy. Overall, this comprehensive review strives to provide up-to-date information to an audience working at the juncture of biomaterials and cancer immunotherapy. STATEMENT OF SIGNIFICANCE: : Cancer immunotherapy possesses incredible potential and has successfully transitioned into a clinically lucrative alternative to conventional anti-cancer therapies. With new immunotherapeutics getting rapid clinical approval, fundamental problems associated with the dynamic nature of the immune system (like limited clinical response rates and autoimmunity-related adverse effects) have remained unanswered. In this context, treatment approaches that focus on modulating the compromised immune components within the tumor microenvironment have garnered significant attention amongst the scientific community. This review aims to provide a critical discussion on how various biomaterials (polymer-based, lipid-based, carbon-based, cell-derived, etc.) can be employed along with immunostimulatory agents to design innovative platforms for selective immunotherapy directed against cancer and cancer stem cells.
... Immunosuppression within the tumor microenvironment (TME) play a crucial part in promoting the growth, invasion and metastasis of tumors [1][2][3][4]. Although some chemotherapeutic agents can induce immunogenic cell death (ICD) in addition to their direct cytotoxic effects to tumor cells, the resulting innate immune response is usually very weak owing to the strongly immunosuppressive tumor microenvironment (ITM). ...
Myeloid-derived suppressor cells (MDSCs) have played a significant role in facilitating tumor immune escape and inducing an immunosuppressive tumor microenvironment. Eliminating MDSCs and tumor cells remains a major challenge in cancer immunotherapy. A novel approach has been developed using gemcitabine-celecoxib twin drug-based nano-assembled carrier-free nanoparticles (GEM-CXB NPs) for dual depletion of MDSCs and tumor cells in breast cancer chemoimmunotherapy. The GEM-CXB NPs exhibit prolonged blood circulation, leading to the preferential accumulation and co-release of GEM and CXB in tumors. This promotes synergistic chemotherapeutic activity by the proliferation inhibition and apoptosis induction against 4T1 tumor cells. In addition, it enhances tumor immunogenicity by immunogenic cell death induction and MDSC-induced immunosuppression alleviation through the depletion of MDSCs. These mechanisms synergistically activate the antitumor immune function of cytotoxic T cells and natural killer cells, inhibit the proliferation of regulatory T cells, and promote the M2 to M1 phenotype repolarization of tumor-associated macrophages, considerably enhancing the overall antitumor and anti-metastasis efficacy in BALB/c mice bearing 4T1 tumors. The simplified engineering of GEM-CXB NPs, with their dual depletion strategy targeting immunosuppressive cells and tumor cells, represents an advanced concept in cancer chemoimmunotherapy.
Graphical Abstract
... Immunotherapy promotes macrophage activation to phagocytose cancer cells and controls tumor growth. In another recent study, a dual-functional immunotherapeutic gel was prepared as a therapy for the postsurgical treatment of colorectal cancer [293,296]. The gel contained poly(l-glutamic acid)-g-methoxy PEG/phenylboronic acid and tannic acid and was loaded with anti-OX40 antibody. ...
Polymeric in situ forming depots have emerged as highly promising drug delivery systems for long-acting applications. Their effectiveness is attributed to essential characteristics such as biocompatibility, biodegradability, and the ability to form a stable gel or solid upon injection. Moreover, they provide added versatility by complementing existing polymeric drug delivery systems like micro- and nanoparticles. The formulation's low viscosity facilitates manufacturing unit operations and enhances delivery efficiency, as it can be easily administered via hypodermic needles. The release mechanism of drugs from these systems can be predetermined using various functional polymers. To enable unique depot design, numerous strategies involving physiological and chemical stimuli have been explored. Important assessment criteria for in situ forming depots include biocompatibility, gel strength and syringeability, texture, biodegradation, release profile, and sterility. This review focuses on the fabrication approaches, key evaluation parameters, and pharmaceutical applications of in situ forming depots, considering perspectives from academia and industry. Additionally, insights about the future prospects of this technology are discussed.
... Compared to traditional cancer treatments, immunotherapy is safer and more effective. Mainstream immunotherapy-based treatments include immune checkpoint blockers and CAR-T therapy, while cancer vaccines with molecular adjuvants are also being explored [202]. However, non-specific inflammation, autoimmune-like disorders, and severe toxicity-related disorders are critical drawbacks of immunotherapy. ...
Achieving precise cancer theranostics necessitates the rational design of smart nanosystems that ensure high biological safety and minimize non-specific interactions with normal tissues. In this regard, “bioinspired” membrane-coated nanosystems have emerged as a promising approach, providing a versatile platform for the development of next-generation smart nanosystems. This review article presents an in-depth investigation into the potential of these nanosystems for targeted cancer theranostics, encompassing key aspects such as cell membrane sources, isolation techniques, nanoparticle core selection, approaches for coating nanoparticle cores with the cell membrane, and characterization methods. Moreover, this review underscores strategies employed to enhance the multi-functionality of these nanosystems, including lipid insertion, membrane hybridization, metabolic engineering, and genetic modification. Additionally, the applications of these bioinspired nanosystems in cancer diagnosis and therapeutics are discussed, along with the recent advances in this field. Through a comprehensive exploration of membrane-coated nanosystems, this review provides valuable insights into their potential for precise cancer theranostics
Immune dysregulation is a pivotal factor in the onset and progression of various diseases. In cancer, the immune system's inability to discern and eliminate abnormal cells leads to uncontrolled tumor growth. When faced with resilient pathogens or harmful toxins, the immune system encounters challenges in clearance and neutralization. Achieving a delicate balance of pro‐inflammatory and anti‐inflammatory signals is essential in managing a range of disorders and diseases. Like in other biomedical research domains, nanotechnology has provided innovative approaches for rebalancing host immunity. Among the plethora of nanotechnology‐based interventions, the concept of cell membrane‐coated nanoparticles holds significant potential for immunomodulatory applications owing to their biomimetic properties that allow for precise interaction with the compromised immune system. This review thoroughly examines the potential of novel nanosystems for immune modulation. The exploration covers crucial elements, including the origins and characteristics of cell membranes, the methods employed for their procurement and coating, physicochemical/biological characterization techniques, and enhancement of their therapeutic efficacy via functionalization. Subsequently, case studies‐based analysis of utilizing these bioinspired nanosystems in tackling different conditions caused by immune disturbance has been comprehensively discussed.
The glioblastoma stem cell (GSC) population in
glioblastoma multiforme (GBM) poses major complication in
clinical oncology owing to increased resistance to chemo-
therapeutic drugs, thereby limiting treatment in patients with
recurring glioblastoma. To completely eradicate glioblastoma, a
single therapy module is not enough; therefore, there is a need to
develop a multimodal approach to eliminate bulk tumors along
with the CSC population. With an aim to target transporters
associated with multidrug resistance (MDR), such as P-
glycoprotein (P-gp), a small-molecule inhibitor, reversan (RV)
was used along with multifunctional magnetic nanoparticles
(MNPs) for hyperthermia (HT) therapy and targeted drug
delivery. Higher efflux of free doxorubicin (Dox) from the cells was stabilized by encapsulation in PPS-MnFe nanoparticles, whose physicochemical properties were determined by dynamic light scattering (DLS) and transmission electron microscopy (TEM). Treatment with RV also enhanced the cellular uptake of PPS-MnFe-Dox, whereas RV and magnetic hyperthermia (MHT) together showed prolonged retention of fluorescence dye, Rhodamine123 (R123), in glioblastoma cells compared with individual treatment. Overall, in this work, we demonstrated the synergistic action of RV and HT to combat MDR in GBM and GSCs, and chemo-hyperthermia therapy enhanced the cytotoxic effect of the chemotherapeutic drug Dox (with lower effective concentration) and induced a higher degree of apoptosis compared to single-drug dosage.
Cancer is a complex illness that presents significant challenges in its understanding and treatment. The classic definition, "a group of diseases characterized by the uncontrolled growth and spread of abnormal cells in the body," fails to convey the intricate interaction between the many entities involved in cancer. Recent advancements in the field of cancer research have shed light on the role played by individual cancer cells and the tumor microenvironment as a whole in tumor development and progression. This breakthrough enables the utilization of the tumor and its components as biological tools, opening new possibilities. This article delves deeply into the concept of "tumor-derived systems”, an umbrella term for tools sourced from the tumor that aid in combatting it. It includes cancer cell membrane-coated nanoparticles (for tumor theranostics), extracellular vesicles (for tumor diagnosis/therapy), tumor cell lysates (for cancer vaccine development), and engineered cancer cells/organoids (for cancer research). This review seeks to offer a complete overview of the tumor-derived materials that are utilized in cancer research, as well as their current stages of development and implementation. It is aimed primarily at researchers working at the interface of cancer biology and biomedical engineering, and it provides vital insights into this fast-growing topic.
Graphical Abstract
The primary cause of cisplatin resistance in liver cancer is reduced intracellular drug accumulation and altered DNA repair/apoptosis signaling. Existing strategies to reverse cisplatin resistance have limited efficacy, as they target individual factors. This study proposes a drug delivery system consisting of a cisplatin core, a silica shell with a tetra-sulfide bond, and a PEG-coated surface (Core/shell-PGCN). The system is designed to consume glutathione (GSH) and reduce cisplatin excretion from cells, thereby overcoming acquired cisplatin resistance. In addition, Core/shell-PGCN incorporates PTC-209 (Core/shell-PGCN@PTC-209), a Bmi1 inhibitor that suppresses liver cancer stem cells (CSC), to mitigate DNA repair/apoptosis signaling and reverse intrinsic cisplatin resistance. In vivo and in vitro results demonstrate that Core/shell-PGCN@PTC-209 can comprehensively regulate GSH and CSC, reverse intrinsic and acquired cisplatin resistance, and enhance the efficacy of cisplatin in treating liver cancer. This "inner cultivation, outer action" approach may offer a new strategy for reversing cisplatin resistance in liver cancer. STATEMENT OF SIGNIFICANCE: Cisplatin resistance is widely observed in liver cancer (HCC) chemotherapy, with two mechanisms identified: acquired and intrinsic. Most strategies aimed at overcoming cisplatin resistance focus on a single perspective. This study introduces a core-shell drug delivery system (DDS) combined with HCC stem cell inhibitors, which can effectively address cisplatin resistance in HCC by targeting both acquisition and internality. Specifically, the core-shell drug delivery system can impede cisplatin efflux by neutralizing the acquired resistance factor (GSH), thus overcoming acquired resistance. Additionally, HCC stem cell inhibitors can reverse intrinsic resistance by inhibiting HCC stem cells. Therefore, this study contributes to the application of DDS in combating drug resistance in HCC and enhances its potential for clinical implementation.
Cancer immunotherapies have reshaped the paradigm for cancer treatment over the past decade. Among them, therapeutic cancer vaccines that aim to modulate antigen presenting cells (e.g., dendritic cells (DCs)) and subsequent T cell priming processes were among the first FDA‐approved cancer immunotherapies. However, despite showing benign safety profiles and the capability to generate antigen‐specific humoral and cellular responses, cancer vaccines have been limited by the modest therapeutic efficacy, especially for immunologically cold solid tumors. One key challenge lies in the identification of tumor‐specific antigens, which involves a costly and lengthy process of tumor cell isolation, DNA/RNA extraction, sequencing, mutation analysis, epitope prediction, peptide synthesis, and antigen screening. To address these issues, in situ cancer vaccines have been actively pursued to generate endogenous antigens directly from tumors and utilize the generated tumor antigens to elicit potent cytotoxic T lymphocyte (CTL) response. Biomaterials‐based in situ cancer vaccines, in particular, have achieved significant progress by taking advantage of biomaterials that can synergize antigens and adjuvants, troubleshoot delivery issues, home and manipulate immune cells in situ. This review will provide an overview of biomaterials‐based in situ cancer vaccines, either living or artificial materials, under development or in the clinic, and discuss the design criteria for in situ cancer vaccines to achieve improved CTL response and antitumor efficacy. This article is protected by copyright. All rights reserved
Cancer immunotherapies have revolutionized the treatment of numerous cancers, with exciting results often superior to conventional treatments, such as surgery and chemotherapy. Despite this success, limitations such as limited treatment persistence and toxic side effects remain to be addressed to further improve treatment efficacy. Biomaterials offer numerous advantages in the concentration, localization and controlled release of drugs, cancer antigens, and immune cells in order to improve the efficacy of these immunotherapies. This review summarizes and highlights the most recent advances in the use of biomaterials for immunotherapies including drug delivery and cancer vaccines, with a particular focus on biomaterials for immune cell delivery.
Phospholipase D (PLD) is a potential therapeutic target against cancer. However, the contribution of PLD inhibition to the antitumor response remains unknown. We developed a potent and selective PLD1 inhibitor based on computer-aided drug design. The inhibitor enhanced apoptosis in colorectal cancer (CRC) cells but not in normal colonic cells, and in vitro cardiotoxicity was not observed. The inhibitor downregulated the Wnt/β-catenin signaling pathway and reduced the migration, invasion, and self-renewal capacity of CRC cells. In cancer, therapeutic engagement of immunogenic cell death (ICD) leads to more effective responses by eliciting the antitumor immunity of T cells. The CRC cells treated with the inhibitor showed hallmarks of ICD, including downregulation of “do not eat-me” signals (CD24, CD47, programmed cell death ligand 1 [PD-L1]), upregulation of “eat-me” signal (calreticulin), release of high-mobility group Box 1, and ATP. PLD1 inhibition subsequently enhanced the phagocytosis of cancer cells by macrophages through the surface expression of costimulatory molecules; as a result, the cancer cells were more susceptible to cytotoxic T-cell-mediated killing. Moreover, PLD1 inhibition attenuated colitis-associated CRC and orthotopically injected tumors, probably by controlling multiple pathways, including Wnt signaling, phagocytosis checkpoints, and immune signaling. Furthermore, combination therapy with a PLD1 inhibitor and an anti-PD-L1 antibody further enhanced tumor regression via immune activation in the tumor environment. Collectively, in this study, PLD1 was identified as a critical regulator of the tumor microenvironment in colorectal cancer, suggesting the potential of PLD1 inhibitors for cancer immunotherapy based on ICD and immune activation. PLD1 inhibitors may act as promising immune modulators in antitumor treatment via ICD.
The most immune cells infiltrating tumor microenvironment (TME), tumor‐associated macrophages (TAMs) closely resemble immunosuppressive M2‐polarized macrophages. Moreover, tumor cells exhibit high expression of CD47 “don't eat me” signal, which obstructs macrophage phagocytosis. The precise and efficient activation of TAMs is a promising approach to tumor immunotherapy; however re‐education of macrophages remain a challenge. Bacteria‐derived outer membrane vesicles (OMVs) are highly immunogenic nanovesicles that can robustly stimulate macrophages. Here, we report an OMV‐based controllable two‐way adaptor, in which a CD47 nanobody (CD47nb) was fused onto OMV surface (OMV‐CD47nb), with the outer surface coated with a polyethylene glycol (PEG) layer containing diselenide bonds (PEG/Se) to form PEG/Se@OMV‐CD47nb. The PEG/Se layer modification not only mitigated the immunogenicity of OMV‐CD47nb, thereby remarkedly increasing the dose that could be administered safely through intravenous injection, but also equipped the formulation with radiation‐triggered controlled release of OMV‐CD47nb. Application of radiation to tumors in mice injected with the nanoformulation resulted in remodeling of TME. As two‐way adaptors, OMV‐CD47nb activated TAM phagocytosis of tumor cells via multiple pathways, including induction of M1 polarization and blockade of “don't eat me” signal. Moreover, this activation of TAMs resulted in the stimulation of T cell‐mediated antitumor immunity through effective antigen presentation. This article is protected by copyright. All rights reserved
Although nano-immunotherapy has advanced dramatically in recent times, there remain two significant hurdles related to immune systems in cancer treatment, such as (namely) inevitable immune elimination of nanoplatforms and severely immunosuppressive microenvironment with low immunogenicity, hampering the performance of nanomedicines. To address these issues, several immune-regulating camouflaged nanocomposites have emerged as prevailing strategies due to their unique characteristics and specific functionalities. In this review, we emphasize the composition, performances, and mechanisms of various immune-regulating camouflaged nanoplatforms, including polymer-coated, cell membrane-camouflaged, and exosome-based nanoplatforms to evade the immune clearance of nanoplatforms or upregulate the immune function against the tumor. Further, we discuss the applications of these immune-regulating camouflaged nanoplatforms in directly boosting cancer immunotherapy and some immunogenic cell death-inducing immunotherapeutic modalities, such as chemotherapy, photothermal therapy, and reactive oxygen species-mediated immunotherapies, highlighting the current progress and recent advancements. Finally, we conclude the article with interesting perspectives, suggesting future tendencies of these innovative camouflaged constructs towards their translation pipeline.
With an understanding of immunity in the tumor microenvironment, immunotherapy turns out to be a powerful tool in the clinic to treat many cancers. The strategies applied in cancer immunotherapy mainly include blockade of immune checkpoints, adoptive transfer of engineered cells, such as T cells, natural killer cells, and macrophages, cytokine therapy, cancer vaccines, and oncolytic virotherapy. Many factors, such as product price, off-target side effects, immunosuppressive tumor microenvironment, and cancer cell heterogeneity, affect the treatment efficacy of immunotherapies against cancers. In addition, some treatments, such as chimeric antigen receptor (CAR) T cell therapy, are more effective in treating patients with lymphoma, leukemia, and multiple myeloma rather than solid tumors. To improve the efficacy of targeted immunotherapy and reduce off-target effects, delivery systems for immunotherapies have been developed in past decades using tools such as nanoparticles, hydrogel matrix, and implantable scaffolds. This review first summarizes the currently common immunotherapies and their limitations. It then synopsizes the relative delivery systems that can be applied to improve treatment efficacy and minimize side effects. The challenges, frontiers, and prospects for applying these delivery systems in cancer immunotherapy are also discussed. Finally, the application of these approaches in clinical trials is reviewed.
Nanovaccines, a new generation of vaccines that use nanoparticles as carriers and/or adjuvants, have been widely used in the prevention and treatment of various diseases, including cancer. Nanovaccines have sparked considerable interest in cancer therapy due to a variety of advantages, including improved access to lymph nodes (LN), optimal packing and presentation of antigens, and induction of a persistent anti-tumor immune response. As a delivery system for cancer vaccines, various types of nanoparticles have been designed to facilitate the delivery of antigens and adjuvants to lymphoid organs and antigen-presenting cells (APCs). Particularly, some types of nanoparticles are able to confer an immune-enhancing capability and can themselves be utilized for adjuvant-like effect for vaccines, suggesting a direction for a better use of nanomaterials and the optimization of cancer vaccines. However, this role of nanoparticles in vaccines has not been well studied. To further elucidate the role of self-adjuvanting nanovaccines in cancer therapy, we review the mechanisms of antitumor vaccine adjuvants with respect to nanovaccines with self-adjuvanting properties, including enhancing cross-presentation, targeting signaling pathways, biomimicking of the natural invasion process of pathogens, and further unknown mechanisms. We surveyed self-adjuvanting cancer nanovaccines in clinical research and discussed their advantages and challenges. In this review, we classified self-adjuvanting cancer nanovaccines according to the underlying immunomodulatory mechanism, which may provide mechanistic insights into the design of nanovaccines in the future.
Graphical Abstract
Background
Triple-negative breast cancer (TNBC) is a highly aggressive subtype of breast cancer with poor prognosis and limited treatment. As a major component of the tumor microenvironment, tumor-associated macrophages (TAMs) play an important role in facilitating the aggressive behavior of TNBC. This study aimed to explore the novel mechanism of TAMs in the regulation of epithelial–mesenchymal transition (EMT) and cancer stem cell (CSC) properties in TNBC.
Methods
Expression of the M2-like macrophage marker CD163 was evaluated by immunohistochemistry in human breast cancer tissues. The phenotype of M2 macrophages polarized from Tohoku-Hospital-Pediatrics-1 (THP1) cells was verified by flow cytometry. Transwell assays, wound healing assays, western blotting, flow cytometry, ELISA, quantitative polymerase chain reaction (qPCR), luciferase reporter gene assays, and immunofluorescence assays were conducted to investigate the mechanism by which TAMs regulate EMT and CSC properties in BT549 and HCC1937 cells.
Results
Clinically, we observed a high infiltration of M2-like tumor-associated macrophages in TNBC tissues and confirmed that TAMs were associated with unfavorable prognosis in TNBC patients. Moreover, we found that conditioned medium from M2 macrophages (M2-CM) markedly promoted EMT and CSC properties in BT549 and HCC1937 cells. Mechanistically, we demonstrated that chemokine (C–C motif) ligand 2 (CCL2) secretion by TAMs activated Akt signaling, which in turn increased the expression and nuclear localization of β-catenin. Furthermore, β-catenin knockdown reversed TAM-induced EMT and CSC properties.
Conclusions
This study provides a novel mechanism by which TAMs promote EMT and enhance CSC properties in TNBC via activation of CCL2/AKT/β-catenin signaling, which may offer new strategies for the diagnosis and treatment of TNBC.
Immunotherapy and vaccines have revolutionized disease treatment and prevention. Vaccines against infectious diseases have been in use for several decades. In contrast, only few cancer vaccines have been approved for human use. These include preventative vaccines against infectious agents associated with cancers, and therapeutic vaccines used as immunotherapy agents to treat cancers. Challenges in developing cancer vaccines include heterogeneity within and between cancer types, screening and identification of appropriate tumour-specific antigens, and the choice of vaccine delivery platforms. Recent advances in all of these areas and the lessons learnt from COVID-19 vaccines have significantly boosted interest in cancer vaccines. Further advances in these areas are expected to facilitate development of effective novel cancer vaccines. In this review, we aim to discuss the past, the present, and the future of cancer vaccines.
Adoptive cell therapy (ACT) constitutes a major breakthrough in cancer management that has expanded in the past years due to impressive results showing durable and even curative responses for some patients with hematological malignancies. ACT leverages antigen specificity and cytotoxic mechanisms of the immune system, particularly relying on the patient´s T lymphocytes to target and eliminate malignant cells. This personalized therapeutic approach exemplifies the success of the joint effort of basic, translational and clinical researchers that has turned the patient´s immune system into a great ally in the search for a cancer cure. Adoptive cell therapies are constantly improving to reach a maximum beneficial clinical response. Despite being very promising therapeutic options for certain types of cancers, mainly melanoma and hematological malignancies, these individualized treatments still present several shortcomings including elevated costs, technical challenges, management of adverse side effects and a limited population of responder patients. Thus, it is crucial to discover and develop reliable and robust biomarkers to specifically and sensitively pinpoint the patients that will benefit the most from ACT, as well as those that are at higher risk of developing potentially serious toxicities. Although unique readouts of infused cell therapy success have not yet been identified, certain characteristics from the adoptive cells, the tumor and/or the tumor microenvironment have been recognized to predict patients' outcome upon ACT. Here, we comment on the importance of biomarkers to predict ACT chances of success to maximize efficacy of treatments and increase patients' survival.
Exploration of tumor immunity leads to the development of immune checkpoint inhibitors and cell-based immunotherapies which improve the clinical outcomes in several tumor types. However, the poor clinical efficacy of these treatments observed for other tumors could be attributed to the inherent complex tumor microenvironment (TME), cellular heterogeneity, and stemness driven by cancer stem cells (CSCs). CSC-specific characteristics provide the bulk tumor surveillance and resistance to entire eradication upon conventional therapies. CSCs-immune cells crosstalk creates an immunosuppressive TME that reshapes the stemness in tumor cells, resulting in tumor formation and progression. Thus, identifying the immunological features of CSCs could introduce the therapeutic targets with powerful antitumor responses. In this review, we summarized the role of immune cells providing CSCs to evade tumor immunity, and then discussed the intrinsic mechanisms represented by CSCs to promote tumors’ resistance to immunotherapies. Then, we outlined potent immunotherapeutic interventions followed by a perspective outlook on the use of nanomedicine-based drug delivery systems for controlled modulation of the immune system.
Despite the encouraging breakthroughs in medical development, cancer remains one of the principle causes of death and threatens human health around the world. Conventional treatment strategies often kill cancer cells at the expense of serious adverse effects or great pain, which yet is not able to achieve an effective cure. Therefore, it is urgent to seek for other novel anticancer approaches to improve the survival rate and life quality of cancer patients. During the past decades, nanotechnology has made tremendous progress in cancer therapy due to many advantages such as targeted drug delivery, decreased dosage-related adverse effects and prolonged drug circulation time. In the context of nanomedicine, carbon nanomaterials occupy very significant positions. Owing to their innate outstanding optical, thermal, electronic, and mechanic features, easy functionalization possibility and large surface for drug loading, carbon nanomaterials serve as not only drug carriers, but also multifunctional platforms to combine with diverse treatment and diagnosis modalities against cancer. Therefore, developing more carbon-based nanoplatforms plays a critical role in cancer theranostics and an update overview that summarizes the recent achievement of carbon nanomaterial-mediated anticancer theranostic approaches is of necessity. In this review, five typical and widely investigated carbon nanomaterials including graphene, graphdiyne, fullerene, carbon nanotubes and carbon quantum dots are introduced in detail from the aspect of treatment strategies based on both cancer cells and tumor microenvironment-involved therapeutic targets. Meanwhile, modern diagnostic methods and clinical translatability of carbon nanomaterials will be highlighted as well.
Immunotherapy holds enormous promise to create a new outlook of cancer therapy by eliminating tumors via activation of the immune system. In immunotherapy, polymeric systems play a significant role in improving antitumor efficacy and safety profile. Polymeric systems possess many favorable properties, including magnificent biocompatibility and biodegradability, structural and component diversity, easy and controllable fabrication, and high loading capacity for immune-related substances. These properties allow polymeric systems to perform multiple functions in immunotherapy, such as immune stimulants, modifying and activating T cells, delivery system for immune cargos, or as an artificial antigen-presenting cell. Among diverse immunotherapies, immune checkpoint inhibitors, chimeric antigen receptor (CAR) T cell, and oncolytic virus recently have been dramatically investigated for their remarkable success in clinical trials. In this report, we review the monotherapy status of immune checkpoint inhibitors, CAR-T cell, and oncolytic virus, and their current combination strategies with diverse polymeric systems.
T cells require a co‐stimulatory signal in addition to T‐cell receptor (TCR) stimulation to achieve full activation. While most studies focus on the co‐stimulatory receptor CD28, little is known about the role of the other co‐stimulatory receptors in T‐cell signaling. A deeper understanding of how co‐stimulatory receptor signaling cooperates with TCR signaling could improve the ability to control T‐cell function and benefit the design of T‐cell based immunotherapies. Artificial antigen presenting cells (aAPCs) enable tight control over the signals given to T cells. In this study, filamentous polyisocyanopeptide (PIC) polymers (immunofilaments) are used as nanosized aAPCs to study the role of the engagement of six distinct co‐stimulatory molecules on human T‐cell phenotype, function, and fate in the context of TCR signaling. The immunofilaments highlight important roles for CD28 and CD2 signaling in T‐cell priming, proliferation, cytokine production, and multifunctionality. Taken together, this work provides insight into the role of combined TCR and co‐stimulation on T‐cell phenotype, function, and fate using immunofilaments. Notably, the findings on the roles of co‐stimulatory molecule function can be used for the rational design of future cancer immunotherapies.
Background
Dendritic cells (DCs) are central for the initiation and regulation of innate and adaptive immunity in the tumor microenvironment. As such, many kinds of DC-targeted vaccines have been developed to improve cancer immunotherapy in numerous clinical trials. Targeted delivery of antigens and adjuvants to DCs in vivo represents an important approach for the development of DC vaccines. However, nonspecific activation of systemic DCs and the preparation of optimal immunodominant tumor antigens still represent major challenges.
Methods
We loaded the immunogenic cell death (ICD) inducers human neutrophil elastase (ELANE) and Hiltonol (TLR3 agonist) into α-lactalbumin (α-LA)-engineered breast cancer-derived exosomes to form an in situ DC vaccine (HELA-Exos). HELA-Exos were identified by transmission electron microscopy, nanoscale flow cytometry, and Western blot analysis. The targeting, killing, and immune activation effects of HELA-Exos were evaluated in vitro. The tumor suppressor and immune-activating effects of HELA-Exos were explored in immunocompetent mice and patient-derived organoids.
Results
HELA-Exos possessed a profound ability to specifically induce ICD in breast cancer cells. Adequate exposure to tumor antigens and Hiltonol following HELA-Exo-induced ICD of cancer cells activated type one conventional DCs (cDC1s) in situ and cross-primed tumor-reactive CD8 ⁺ T cell responses, leading to potent tumor inhibition in a poorly immunogenic triple negative breast cancer (TNBC) mouse xenograft model and patient-derived tumor organoids.
Conclusions
HELA-Exos exhibit potent antitumor activity in both a mouse model and human breast cancer organoids by promoting the activation of cDC1s in situ and thus improving the subsequent tumor-reactive CD8 ⁺ T cell responses. The strategy proposed here is promising for generating an in situ DC-primed vaccine and can be extended to various types of cancers.
Graphic Abstract
Scheme 1. Schematic illustration of HELA-Exos as an in situ DC-primed vaccine for breast cancer. (A) Allogenic breast cancer-derived exosomes isolated from MDA-MB-231 cells were genetically engineered to overexpress α-LA and simultaneously loaded with the ICD inducers ELANE and Hiltonol (TLR3 agonist) to generate HELA-Exos. (B) Mechanism by which HELA-Exos activate DCs in situ in a mouse xenograft model ofTNBC. HELA-Exos specifically homed to the TME and induced ICD in cancer cells, which resulted in the increased release of tumor antigens, Hiltonol, and DAMPs, as well as the uptake of dying tumor cells by cDC1s. The activated cDC1s then cross-primed tumor-reactive CD8+ T cell responses. (C) HELA-Exos activated DCs in situ in the breast cancer patient PBMC-autologous tumor organoid coculture system. Abbreviations: DCs: dendritic cells; α-LA: α-lactalbumin; HELA-Exos: Hiltonol-ELANE-α-LA-engineered exosomes; ICD: immunogenic cell death; ELANE: human neutrophil elastase; TLR3: Toll-like receptor 3; TNBC: triple-negative breast cancer; TME: tumor microenvironment; DAMPs: damage-associated molecular patterns; cDC1s: type 1 conventional dendritic cells; PBMCs: peripheral blood mononuclear cells
Both tumor‐associated macrophages (TAMs) and hypoxia condition severely restrict the antitumor potency during cancer immunotherapy. It is essential to overcome the two issues for improving therapeutic efficacy. In this study, we built hollow mesoporous Prussian blue (HMPB) nanosystem with mannose decoration and hydroxychloroquine (HCQ) adsorption to form Man‐HMPB/HCQ. It could facilitate cellular internalization via mannose‐receptor mediated endocytosis and induce TAM polarization via iron ion/HCQ release with HMPB degradation. The hybrid macrophage and thylakoid (TK) membrane was camouflaged on Man‐HMPB/HCQ surface, denoted as TK‐M@Man‐HMPB/HCQ, to reduce in vivo reticuloendothelial system (RES) uptake, enhance tumor accumulation and mitigate hypoxia. The in vivo results indicated that TK‐M@Man‐HMPB/HCQ notably inhibited tumor growth, induced TAM polarization, facilitated cytotoxic T lymphocytes infiltration and alleviated hypoxia microenvironment. The rational design may provide a new pathway to modulate TME for promoting cancer immunotherapy effects. This article is protected by copyright. All rights reserved
Liposomes are well-recognized and essential nano-sized drug delivery systems. Liposomes are phospholipid vesicles comprised of cell membrane components and have been employed as artificial cell models to mimic structure and functions of cells and are of immense use in various biological analyses. Liposomes acquire great advantages and provide wide range of applications as useful drug carriers in pre-clinical and clinical trials. This review summarizes exclusively on scalable techniques for liposome preparation and focuses on the strengths and limitations with respect to industrial applicability. Also, this review discusses the updated recent advancements in biomedical applications with a mention of key highlights of commercially available formulations, clinical trials and patents in recent past. Furthermore, this review also provides brief information of the classification, composition and characterization of liposomes.
Though increasing understanding and remarkable clinical successes have been made, enormous challenges remain to be solved in the field of cancer immunotherapy. In this context, biomaterial-based immunomodulatory strategies are being developed to boost antitumor immunity. For the local immunotherapy, macroscale biomaterial scaffolds with 3D network structures show great superiority in the following aspects: facilitating the encapsulation, localized delivery, and controlled release of immunotherapeutic agents and even immunocytes for more efficient immunomodulation. The concentrating immunomodulation in situ could minimize systemic toxicities, but still exert abscopal effects to harness the power of overall anticancer immune response for eradicating malignancy. To promote such promising immunotherapies, the design requirements of macroscale 3D scaffolds should comprehensively consider their physicochemical and biological properties, such as porosity, stiffness, surface modification, cargo release kinetics, biocompatibility, biodegradability, and delivery modes. To date, increasing studies have focused on the relationships between these parameters and the biosystems which will guide/assist the 3D biomaterial scaffolds to achieve the desired immunotherapeutic outcomes. In this review, by highlighting some recent achievements, we summarized the latest advances in the development of various 3D scaffolds as niches for cancer immunotherapy. We also discussed opportunities, challenges, current trends, and future perspectives in 3D macroscale biomaterial scaffold-assisted local treatment strategies. More importantly, this review put more efforts to illustrate how the 3D biomaterial systems affect to modulate antitumor immune activities, where we discussed how significant the roles and behaviours of 3D macroscale scaffolds towards in situ cancer immunotherapy in order to direct the design of 3D immunotherapeutic.
Background
Inspired by nature, the biomimetic approach has been incorporated into drug nanocarriers for cancer targeted chemotherapy. The nanocarriers are cloaked in cell membranes, which enables them to incorporate the functions of natural cells.
Key scientific concepts of review
Nanocarriers surface engineered with cell membranes have emerged as a fascinating source of materials for cancer targeted chemotherapy. A distinctive characteristic of cell membrane-coated nanocarriers (CMCNs) is that they include carbohydrates, proteins, and lipids, in addition to being biocompatible. CMCNs are capable of interacting with the complicated biological milieu of the tumor because they contain the signaling networks and intrinsic functions of their parent cells. Numerous cell membranes have been investigated for the purpose of masking nanocarriers with membranes, and various tumor-targeting methods have been devised to improve cancer targeted chemotherapy. Moreover, the diverse structure of the membrane from different cell sources broadens the spectrum of CMCNs and offers an entirely new class of drug-delivery systems.
Aim of review
This review will describe the manufacturing processes for CMCNs and the therapeutic uses for different kinds of cell membrane-coated nanocarrier-based drug delivery systems, as well as addressing obstacles and future prospects.
Graphical Abstract
Multiple biological barriers must be considered in the design of nanomedicines, including prolonged blood circulation, efficient accumulation at the target site, effective penetration into the target tissue, selective uptake of the nanoparticles into target cells, and successful endosomal escape. However, different particle sizes, surface chemistries, and sometimes shapes are required to achieve the desired transport properties at each step of the delivery process. In response, this review highlights recent developments in the design of switchable nanoparticles whose size, surface chemistry, shape, or a combination thereof can be altered as a function of time, a disease‐specific microenvironment, and/or via an externally applied stimulus to enable improved optimization of nanoparticle properties in each step of the delivery process. The practical use of such nanoparticles in chemotherapy, bioimaging, photothermal therapy, and other applications is also discussed.
CD44, a non-kinase cell surface transmembrane glycoprotein, has been widely implicated as a cancer stem cell (CSC) marker in several cancers. Cells overexpressing CD44 possess several CSC traits, such as self-renewal and epithelial-mesenchymal transition (EMT) capability, as well as a resistance to chemo- and radiotherapy. The CD44 gene regularly undergoes alternative splicing, resulting in the standard (CD44s) and variant (CD44v) isoforms. The interaction of such isoforms with ligands, particularly hyaluronic acid (HA), osteopontin (OPN) and matrix metalloproteinases (MMPs), drive numerous cancer-associated signalling. However, there are contradictory results regarding whether high or low CD44 expression is associated with worsening clinicopathological features, such as a higher tumour histological grade, advanced tumour stage and poorer survival rates. Nonetheless, high CD44 expression significantly contributes to enhanced tumourigenic mechanisms, such as cell proliferation, metastasis, invasion, migration and stemness; hence, CD44 is an important clinical target. This review summarises current research regarding the different CD44 isoform structures and their roles and functions in supporting tumourigenesis and discusses CD44 expression regulation, CD44-signalling pathways and interactions involved in cancer development. The clinical significance and prognostic value of CD44 and the potential of CD44 as a therapeutic target in cancer are also addressed.
Whole-cell vaccines that provide broad-spectrum antigens have been explored for recent decades. But so far, they have revealed limited success in clinical trials, possibly owing to their inefficiency in targeting immune organs and antigen-presenting cells (APCs). Herein, a facile strategy is developed to convert the whole-cell vaccines into the nanoscale size to promote their lymphatic migration and subsequent intracellular antigen presentation to maximize immune responses. Briefly, the study designs a multiple antigen delivery platform based on alum-induced and cancer/bacterial cell membrane coated protein antigen nanoparticles. Through a simple two-step vortex-sonification method, a universal carrier-free nano-vaccine without additional excipients could be quickly fabricated. After subcutaneous vaccination, the developed nanovaccines rapidly migrate to lymph nodes, leading to their effective uptake by lymph node-resident APCs, and subsequent antigen presentation and activation of downstream immune processes. Overall, the described promising work offers a safe, effective, facile, and widely applicable vaccine strategy, which has great potential for clinical transformation.
Therapies modulating the immune system offer the prospect of treating a wide range of conditions including infectious diseases, cancer and autoimmunity. Biomaterials can promote specific targeting of immune cell subsets in peripheral or lymphoid tissues and modulate the dosage, timing and location of stimulation, thereby improving the safety and efficacy of vaccines and immunotherapies. Here, we review recent advances in biomaterials-based strategies, focusing on targeting of lymphoid tissues, circulating leukocytes, tissue-resident immune cells and immune cells at disease sites. These approaches can improve the potency and efficacy of immunotherapies by promoting immunity or tolerance against different diseases. This Review discusses biomaterials that promote therapeutic targeting of immune cells by modulating the dosage, timing and location of stimulation, thereby improving the safety and efficacy of vaccines and immunotherapies. In immunotherapy, choosing the right target cell, tissue and treatment duration is essential to ensure effective immunomodulation while avoiding toxicity.Biomaterial-mediated targeting of immune cells in lymph nodes improves the potency and efficacy of vaccines by promoting immunity or tolerance.Circulating migratory immune cells can be targeted to perform as living chaperones to carry therapeutics into tissues.Systemic administration or intratumoral injection of nanomaterials and therapeutic depots can selectively accumulate and target immune cells in tumours.Reducing biomaterial complexity is essential to facilitate clinical translation. In immunotherapy, choosing the right target cell, tissue and treatment duration is essential to ensure effective immunomodulation while avoiding toxicity. Biomaterial-mediated targeting of immune cells in lymph nodes improves the potency and efficacy of vaccines by promoting immunity or tolerance. Circulating migratory immune cells can be targeted to perform as living chaperones to carry therapeutics into tissues. Systemic administration or intratumoral injection of nanomaterials and therapeutic depots can selectively accumulate and target immune cells in tumours. Reducing biomaterial complexity is essential to facilitate clinical translation.
Cancer immunotherapies, such as immune checkpoint blockade and chimeric antigen receptor (CAR) T cell therapy, have transformed clinical oncology. However, limited patient response rates and immune-related adverse events remain major clinical challenges. The immunosuppressive tumour microenvironment (TME) has a key role in the response to immunotherapy. The TME of solid tumours can prevent infiltration and negatively affect the activity of immune cells. The immunosuppressive features of the TME can be modulated using biomaterials-based tools that target, respond to and modulate the physicochemical properties of the TME, including hypoxia, acidity, high levels of reactive oxygen species, a dense extracellular matrix and abnormal vasculature. In this Review, we introduce hallmarks of the TME and discuss biomaterials and nanomedicine technologies that can regulate the TME of solid tumours to improve the efficacy of different types of immunotherapy. We outline the remaining challenges in the clinical translation of TME-modulating biomaterials tools and conclude by envisioning future milestones in this field. The tumour microenvironment of solid tumours can prevent immune cell infiltration and negatively affect the efficacy of immunotherapies. This Review discusses the design of biomaterials-based tools that can modulate the physicochemical features of the tumour microenvironment to assist immunotherapies. The immunosuppressive tumour microenvironment (TME) has a crucial role in limiting the therapeutic responses of solid tumours to immunotherapy.The physicochemical features of the TME, including hypoxia, acidity and high reactive oxygen species (ROS) levels, contribute to the immunosuppressive TME.These features of the TME can be modulated by biomaterials and nanomedicine tools to make the TME susceptible to antitumour immune responses.Combining TME-modulating biomaterials-based therapeutics with immunotherapies can improve clinical outcomes and increase patient response rates. The immunosuppressive tumour microenvironment (TME) has a crucial role in limiting the therapeutic responses of solid tumours to immunotherapy. The physicochemical features of the TME, including hypoxia, acidity and high reactive oxygen species (ROS) levels, contribute to the immunosuppressive TME. These features of the TME can be modulated by biomaterials and nanomedicine tools to make the TME susceptible to antitumour immune responses. Combining TME-modulating biomaterials-based therapeutics with immunotherapies can improve clinical outcomes and increase patient response rates.
Cancer vaccines are hypothesized to trigger an immunological reaction against cancerous tissues. The scope of expanded clinical activities in the cancer vaccine research programmes can be acknowledged by the fact that around 2000 trials are registered under clinical cancer vaccines programme. The research activities in the cancer vaccine research area have gained a boost following the marketing authorization of Sipuleucel-T—the very first cancer vaccine in the US and EU. Though the regulatory guidelines for already existing cancer therapies like chemotherapy, radiotherapy are well established. Recently, the guidelines regarding regulatory aspects for cancer vaccines are developed. However, these guidelines are advisory in nature about the clinical requirements. However, the cancer vaccine development is relatively new area of research. There exists a huge scope for innovative strategies in this field. Hence, bilateral talks with the regulatory body are mandatory requirement to discuss and deliberate the clinical development plan on case-by-case basis. Thereby, the specific issues related to the quality of product under development are taken into consideration. All such regulatory aspects pertaining to the development and approval of cancer vaccines are discussed hereby in this chapter.KeywordsT-cellsAntigensCancer vaccinesImmune system
T cells and natural killer (NK) cells have complementary roles in tumor immunity, and dual T cell and NK cell attack thus offers opportunities to deepen the impact of immunotherapy. Recent work has also shown that NK cells play an important role in recruiting dendritic cells to tumors and thus enhance induction of CD8 T cell responses, while IL-2 secreted by T cells activates NK cells. Targeting of immune evasion mechanisms from the activating NKG2D receptor and its MICA and MICB ligands on tumor cells offers opportunities for therapeutic intervention. Interestingly, T cells and NK cells share several important inhibitory and activating receptors that can be targeted to enhance T cell– and NK cell–mediated immunity. These inhibitory receptor-ligand systems include CD161-CLEC2D, TIGIT-CD155, and NKG2A/CD94-HLA-E. We also discuss emerging therapeutic strategies based on inhibitory and activating cytokines that profoundly impact the function of both lymphocyte populations within tumors.
Expected final online publication date for the Annual Review of Immunology, Volume 41 is April 2023. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.
Extracellular vesicles (EVs), phospholipid membrane-bound vesicles, produced by most cells, contribute to cell-cell communication. They transfer several proteins, lipids, and nucleic acids between cells both locally and systemically. Owing to the biocompatibility and immune activity of EVs, therapeutic approaches using these vesicles as drug delivery systems are being developed. Different methods are used to design more effective engineered EVs, which can serve as smart tools in cancer therapy and immunotherapy. Recent progress in the field of targeted-cancer therapy has led to the gradual use of engineered EVs in combinational therapy to combat heterogeneous tumor cells and multifaceted tumor microenvironments. The high plasticity, loading ability, and genetic manipulation capability of engineered EVs have made them the ideal platforms to realize numerous combinations of cancer therapy approaches. From the combination therapy view, engineered EVs can co-deliver chemotherapy with various therapeutic agents to target tumor cells effectively, further taking part in immunotherapy-related cancer combination therapy. However, a greater number of studies were done in pre-clinical platforms and the clinical translation of these studies needs further scrutiny because some challenges are associated with the application of engineered EVs. Given the many therapeutic potentials of engineered EVs, this review discusses their function in various cancer combination therapy and immunotherapy-related cancer combination therapy. In addition, this review describes the opportunities and challenges associated with the clinical application of engineered EVs.
Tumour-associated macrophages are an essential component of the tumour microenvironment and have a role in the orchestration of angiogenesis, extracellular matrix remodelling, cancer cell proliferation, metastasis and immunosuppression, as well as in resistance to chemotherapeutic agents and checkpoint blockade immunotherapy. Conversely, when appropriately activated, macrophages can mediate phagocytosis of cancer cells and cytotoxic tumour killing, and engage in effective bidirectional interactions with components of the innate and adaptive immune system. Therefore, they have emerged as therapeutic targets in cancer therapy. Macrophage-targeting strategies include inhibitors of cytokines and chemokines involved in the recruitment and polarization of tumour-promoting myeloid cells as well as activators of their antitumorigenic and immunostimulating functions. Early clinical trials suggest that targeting negative regulators (checkpoints) of myeloid cell function indeed has antitumor potential. Finally, given the continuous recruitment of myelomonocytic cells into tumour tissues, macrophages are candidates for cell therapy with the development of chimeric antigen receptor effector cells. Macrophage-centred therapeutic strategies have the potential to complement, and synergize with, currently available tools in the oncology armamentarium. Macrophages can promote tumorigenesis and enhance the antitumour response. This Review discusses the molecular mechanisms underlying the reprogramming of macrophages in the tumour microenvironment and provides an overview of macrophage-targeted therapies for the treatment of cancer.
Extracellular vesicles (EVs) are heterogeneous membranous vesicles secreted by living cells that are involved in many physiological and pathological processes as intermediaries for intercellular communication and molecular transfer. Recent studies have shown that EVs can regulate the occurrence and development of tumors by transferring proteins, lipids and nucleic acids to immune cells as signaling molecules. As a new diagnostic biomarker and drug delivery system, EVs have broad application prospects in immunotherapy. In addition, the breakthrough of nanotechnology has promoted the development and exploration of engineered EVs for immune-targeted therapy. Herein, we review the uniqueness of EVs in immune regulation and the engineering strategies used for im-munotherapy and highlight the logic of their design through typical examples. The present situation and challenges of clinical transformation are discussed, and the development prospects of EVs in immunotherapy are proposed. The goal of this review is to provide new insights into the design of immune-regulatory EVs and expand their application in cancer immunotherapy.
Here we present a protocol for the construction and use of two types of nanocarrier based on bacterial membrane materials for cancer vaccine delivery. Cancer vaccines induce tumor regression through triggering the specific T-cell responses against tumor neoantigens, a process that can be enhanced by nanocarrier delivery. Inspired by the body's natural immune defenses against bacterial invasion, we have developed two different types of nanocarrier based on bacterial membrane materials, which employ genetically engineered outer-membrane vesicles (OMVs), or hybrid membrane vesicles containing bacterial cytoplasmic membrane, respectively. The OMV-based nanocarriers can rapidly display different tumor antigens through the surface modified Plug-and-Display system, suitable for customized cancer vaccines when the tumor neoantigens can be identified. The hybrid membrane-based nanocarriers are prepared through fusion of the bacterial cytoplasmic membrane and the primary tumor cell membrane from surgically removed tumor tissues, possessing unique advantages as personalized cancer vaccines when the neoantigens are not readily available. Compared with chemically synthesized nanocarriers such as liposomes and polymer without intrinsic adjuvant properties, owing to the large amounts of pathogen-associated molecular patterns, the two nanocarriers can activate the antigen-presenting cells while delivering multiple antigens, thus inducing effective antigen presentation and robust adaptive immune activation. Excluding bacterial culture and tumor tissue collection, the preparation of OMV- and hybrid membrane-based nanocarriers takes ~8 h and 10 h for tumor vaccine construction, respectively. We also detail how to use these nanocarriers to create cancer nanovaccines and evaluate their immunostimulatory and antitumor effects.
The Enhanced Permeability and Retention (EPR) effect has been recognized as the central paradigm in tumor-targeted delivery in the last decades. In the wake of this concept, nanotechnologies have reached phenomenal levels in research. However, clinical tumors display a poor manifestation of EPR effect. Factors including tumor heterogeneity, complicating tumor microenvironment, and discrepancies between laboratory models and human tumors largely contribute to poor efficiency in tumor-targeted delivery and therapeutic failure in clinical translation. In this article, approaches for evaluation of EPR effect in human tumor were overviewed as guidance to employ EPR effect for cancer treatment. Strategies to augment EPR-mediated tumoral delivery are discussed in different dimensions including enhancement of vascular permeability, depletion of tumor extracellular matrix and optimization of nanoparticle design. Besides, the recent development in alternative tumor-targeted delivery mechanisms are highlighted including transendothelial pathway, endogenous cell carriers and non-immunogenic bacteria-mediated delivery. In addition, the emerging preclinical models better reflect human tumors are introduced. Finally, more rational applications of EPR effect in other disease and field are proposed. This article elaborates on fundamental reasons for the gaps between theoretical expectation and clinical outcomes, attempting to provide some perspective directions for future development of cancer nanomedicines in this still evolving landscape.
The lymphatic system has grasped attention of researchers to a greater extent. The conventional methods of lymphatic delivery are now being modified to include nanotechnology to enhance the targeting of the drug at the specific pathological site. Scientists have worked successfully on different drug loaded nanocarriers that are modulated for the lymphatic system targeting for the treatment of various fatal diseases. Huge strides have been made in methods of delivery of these drugs either individually or in combination along with nanoparticles, therapeutic genes, and vaccines. However, the products introduced for commercial use are almost near nil. Altogether, there are challenges that need to be resolved and studies that are meant to be done for further improvements. The current review focuses on the understanding and pathophysiology of the lymphatic system and changes that occur during disease, drug characteristics, and physicochemical parameters that influence the lymphatic uptake of drugs and different nanocarriers. We further highlight different potential results obtained over the years with nanocarriers and other delivery methods to effectively target the lymphatic system for their therapeutic application. The challenges and drawbacks governing the lack of products available clinically have also been discussed.
Cancer-associated fibroblasts (CAFs)-mediated metabolic support plays a vital role in tumorigenesis. The metabolic network between cancer cells and CAFs may serve as promising targets for cancer therapy. Here, aiming at targeted blockade of the metabolic support of CAFs to cancer cells, a biomimetic nanocarrier is designed by coating solid lipid nanoparticles containing chemotherapeutic paclitaxel (PTX) and glycolysis inhibitor PFK15 with hybrid membranes of cancer cells and activated fibroblasts. The nanoparticles possess outstanding dual-targeting ability which can simultaneously target cancer cells and CAFs. The encapsulated glycolysis inhibitor PFK15 can prevent the glycolysis of cancer cells and CAFs at the same time, thus increasing the chemosensitivity of cancer cells and blocking the metabolic support of CAFs to cancer cells. The results showed that the combination of PTX and PFK15 exhibited synergistic effects and inhibited tumor growth effectively. Moreover, the biomimetic nanoparticles obviously reduced the lactate production in the tumor microenvironment, leading to activated immune responses and enhanced tumor suppression. This work presents a facile strategy to destroy the metabolic network between cancer cells and CAFs, and proves the potential to elevate chemo-immunotherapy by glycolysis inhibition.
Statement of significance
: In many solid tumors, most cancer cells produce energy and carry out biosynthesis through glycolysis, even in aerobic conditions. As the main tumor stromal cells, cancer-associated fibroblasts (CAFs) usually turn oxidative phosphorylation into aerobic glycolysis with metabolic reprogramming and provide high-energy glycolytic metabolites for cancer cells. The metabolic network between cancer cells and CAFs is regarded as the vulnerability among cancer cells. Moreover, lactate produced by cancer cells and CAFs through glycolysis often leads to the immunosuppressive tumor microenvironment. The present study provides an effective approach to destroy the metabolic network between cancer cells and CAFs and greatly improves the antitumor immune response by reducing lactate production, which serves as a promising strategy for combined chemo-immunotherapy mediated by glycolysis.
Vaccination is a proven way to protect individuals against many infectious diseases, as currently highlighted in the global COVID-19 pandemic. Peptides- or small molecule antigen-based vaccination offer advantages over the classical vaccine approaches. However, peptides or small molecules by themselves are generally not sufficiently immunogenic, and thus require an adjuvant to boost an immune response. Several conjugated systems have been developed in recent years to overcome this obstacle. This review summarises different moieties which, when conjugated to peptide antigens, facilitate a specific immune response. Different classes of self-adjuvant moieties are reviewed, including self-assembly peptides, lipids, glycolipids, and polymers.
Basic science breakthroughs in T cell biology and immune-tumor cell interactions ushered in a new era of cancer immunotherapy. Twenty years ago, cancer immunoediting was proposed as a framework to understand the dynamic process by which the immune system can both control and shape cancer and in its most complex form occurs through three phases termed elimination, equilibrium, and escape. During cancer progression through these phases, tumors undergo immunoediting, rendering them less immunogenic and more capable of establishing an immunosuppressive microenvironment. Therefore, cancer immunoediting integrates the complex immune-tumor cell interactions occurring in the tumor microenvironment and sculpts immunogenicity beyond shaping antigenicity. However, with the success of cancer immunotherapy resulting in durable clinical responses in the last decade and subsequent emergence of immuno-oncology as a clinical subspecialty, the phrase "cancer immunoediting" has recently, at times, been inappropriately restricted to describing neoantigen loss by immunoselection. This focus has obscured other mechanisms by which cancer immunoediting modifies tumor immunogenicity. While establishment of the concept of cancer immunoediting and definitive experimental evidence supporting its existence was initially obtained from pre-clinal models in the absence of immunotherapy, cancer immunoediting is a continual process that also occurs during immunotherapy in human cancer patients. Herein, we discuss the known mechanisms of cancer immunoediting obtained from preclinical and clinical data with an emphasis on how a greater understanding of cancer immunoediting may provide insights into immunotherapy resistance and how this resistance can be overcome.
Whole tumor cell-based vaccines include all potential antigen-rich cell lysates to target a specific type of tumor without the need to find the best antigen candidate in protein- or peptide-based vaccines. Preparation of whole tumor cell lysates inducing cell death and inactivating immunosuppressive cytokine secretion from the tumor cells is highly enviable. Generally, modified whole tumor cells, tumor cell-derived exosomes, autologous tumor cell-derived ribonucleic acid, and personalized mutanome-derived tumor antigen are promising immunotherapeutic approaches. Autologous dendritic cells loaded with tumor-associated antigens also induce the generation of immunological memory and antitumor response as an effective method for the treatment of cancer. The present review briefly describes tumor cell-based vaccines as a promising strategy for eradication of cancer cells.
Dendritic cells (DC) are crucial for the priming of T cells and thereby influence adaptive immune responses. Hence, they also represent important players in shaping anti-tumour immune responses. Cancer immunotherapy has been driven over many years by the aim to harness the T-cell stimulatory activity of these crucial antigen-presenting cells (APC). Efficient antigen delivery alone is not sufficient for full engagement of the T-cell stimulatory activity of DC and the inclusion of adjuvants triggering appropriate DC activation is essential to ensure effective anti-tumour immunity induction. While the direct engagement of DC function is a powerful tool for tumour immunotherapy, many therapeutic antibodies, such as antibodies directed against tumour-associated antigens (TAA) and immune checkpoint inhibitors (ICI) have been shown to engage DC function indirectly. The induction of anti-tumour immune responses by TAA-targeting and immune checkpoint inhibitory antibodies is thought to be integral to their therapeutic efficacy. Here, we provide an overview of the immunotherapeutic antibodies in the context of cancer immunotherapy, that has been demonstrated to directly or indirectly engage DC and discuss the current understanding of the functional mechanisms underlying anti-tumour immunity induction by these antibody therapies. In the future, the combination of therapeutic strategies that engage DC function directly and/or indirectly with strategies that allow tumour infiltrating immune effector cells to exert their anti-tumour activity in the tumour microenvironment (TME) may be key for the successful treatment of cancer patients currently not responding to immunotherapeutic antibody treatment.
Oncolytic virotherapy (OVT) is a novel type of immunotherapy that induces anti-tumor responses through selective self-replication within cancer cells and oncolytic virus (OV)-mediated immunostimulation. Notably, talimogene laherparepvec (T-Vec) developed by the Amgen company in 2015, is the first FDA-approved OV product to be administered via intratumoral injection and has been the most successful OVT treatment. However, the systemic administration of OVs still faces huge challenges, including in vivo pre-existing neutralizing antibodies and poor targeting delivery efficacy. Recently, state-of-the-art progress has been made in the development of systemic delivery of OVs, which demonstrates a promising step toward broadening the scope of cancer immunotherapy and improving the clinical efficacy of OV delivery. Herein, this review describes the general characteristics of OVs, focusing on the action mechanisms of OVs as well as the advantages and disadvantages of OVT. The emerging multiple systemic administration approaches of OVs are summarized in the past five years. In addition, the combination treatments between OVT and traditional therapies (chemotherapy, thermotherapy, immunotherapy, and radiotherapy, etc.) are highlighted. Last but not least, the future prospects and challenges of OVT are also discussed, with the aim of facilitating medical researchers to extensively apply the OVT in the cancer therapy.
Remarkable advances have been achieved in the field of nanomedicine and immunotherapy, since it was found that several nanomaterials can modulate the immune system. The main objective of this review is to collect and discuss studies where carbon nanomaterials (CNM), due to their unique structure and composition, revealed to be important tools in cancer treatment, immunostimulation, and immunosuppression of inflammatory or autoimmune diseases. These materials offer several advantages, such as being effective platforms for drug delivery and targeting, immunomodulation, phototherapy, and others. Some effects still need to be upgraded and some questions persist. Positive results were already achieved, although translation to clinics is still needed. The evolution of future investigations may still revolutionize the field of biomedicine.
The generation of DCs with augmented functions is a strategy for obtaining satisfactory clinical outcomes in tumor immunotherapy. We developed a novel synthetic adjuvant comprising a liposome conjugated with a DC-targeting Toll-like-receptor ligand and a pH-sensitive polymer for augmenting cross-presentation. In an in vitro study using mouse DCs, these liposomes were selectively incorporated into DCs, significantly enhanced DC function and activated immune responses to present an epitope of the incorporated antigen on the major histocompatibility complex class I molecules. Immunization of mice with liposomes encapsulating a tumor antigen significantly enhanced antigen-specific cytotoxicity. In tumor-bearing mice, vaccination with liposomes encapsulating a tumor antigen elicited complete tumor remission. Furthermore, vaccination significantly enhanced cytotoxicity, targeting not only the vaccinated antigen but also the other antigens of the tumor cell. These results indicate that liposomes are an ideal adjuvant to develop DCs with considerably high potential to elicit antigen-specific immune responses; they are a promising tool for cancer therapy with neoantigen vaccination.
Extracellular vesicles (EVs) are produced by almost all cell types in vivo or in vitro. Among them, exosomes are small nanovesicles with a lipid bilayer, proteins and RNAs actively involved in cellular communication, suggesting that they may be used both as biomarkers and for therapeutic purposes in diseases such as cancer. Moreover, the idea of using them as drug delivery vehicle arises as a promising field of study. Here, we reviewed recent findings showing the importance of EVs, with special focus in exosomes as biomarkers including the most relevant proteins found in different cancer types and it is discussed the FDA approved tests which use exosomes in clinical practice. Finally, we present an overview of the different chimeric EVs developed in the last few years, demonstrating that they can be conjugate to nanoparticles, biomolecules, cancer drugs, etc., and can be developed for a specific cancer treatment. Additionally, we summarized the clinical trials where EVs are used in the treatment of several cancer types aiming to improve the prognosis of these deadly diseases.
Although chemo-photodynamic therapy demonstrates promising synergetic therapeutic effects in malignant tumors, the light-controlled drug release, synergism and biocompatibility of current nanocarriers are limited. Herein, we report a red light-responsive, self-destructive carrier constructed using polyethylene glycol-modified, diselenide-bridged mesoporous silica nanoparticles. The carrier is co-encapsulated with the chemo-drug doxorubicin and the photosensitizer methylene blue for chemo-photodynamic therapy. Upon low-dose red light irradiation during photodynamic therapy (PDT), the reactive oxygen species (ROS) mediates a diselenide bond cleavage resulting in the degradation of the organosilica matrix and a dual drug release. This, in turn, results in a synergistic chemo-photodynamic performance in vitro and in vivo. More importantly, such cascade chemo-PDT boosts immunogenic cell death and robust anti-tumor immunity responses. Combination with a PD-1 checkpoint blockade further evokes a series of systemic immunity responses that suppress distant tumor growth and the pulmonary metastasis of breast cancer, as well as offer long-term protection against recurrent tumors. The presented work offers a controllable self-destruction nanoplatform for cascade-amplifying chemo-photodynamic therapy in response to external red light radiation.
Cancer nanovaccines as one of immunotherapeutic approaches are able to attack tumors by stimulating tumor-specific immunological responses. However, there still exist multiple challenges to be tackled for cancer nanovaccines to evoke potent antitumor immunity. Particularly, the administration of exogenous materials may cause the off-target immunotherapy responses. In recent years, biomimetic nanovaccines by using cell lysates, cell-derived nanovesicles, or extracted cell membranes as the functional components have received extensive attention. Such nanovaccines based on cell-derived components would show many unique advantages including inherent biocompatibility and the ability to trigger immune responses against a range of tumor-associated antigens. In this review article, we will introduce the recent research progresses of those cell-derived biomimetic nanovaccines for cancer immunotherapy, and discuss the perspectives and challenges associated with the future clinical translation of these emerging vaccine platforms.
Cancer vaccination is an effective way to prevent or cure cancers by inducing strong cellular and humoral immunity with the aid of delivery carriers or adjuvants. Increasing new delivery vehicles and vaccine adjuvants have been developed for immunotherapy as they can enhance immune responses with reduced doses and side effects. In spite of many advantages of cancer immunotherapy, the clinical outcomes of cancer vaccines are still not satisfactory due to insufficient induction of antigen specific T cells. Metalloimmunology may revitalize cancer vaccines and improve their clinical applications considering that nutritional metal ions such as Ca²⁺, K⁺, Fe2+/3+, Zn²⁺, Mn²⁺ play important roles in many key immune processes. As good adjuvants, a wide variety of metals can be incorporated in the formulations of nano-vaccines for the enhanced immunity. Metal-based nanomaterials can also efficiently deliver antigens to antigen-presenting cells for the generation of immunity. In this review, we comprehensively summarized different types of commonly-used metal nanomaterials, as adjuvants or delivery carriers, for the development of effective cancer vaccines. Other applications such as use as contrast agents for bioimaging were also briefly reviewed. Then, their applications for cancer immunotherapy, along with their action mechanisms were systematically discussed.
Nanocarriers with intrinsic immune adjuvant properties can activate the innate immune system while delivering tumor antigen, thus efficiently facilitating antitumor adaptive immunity. Bacteria-derived outer membrane vesicles (OMVs) are an excellent candidate due to their abundance of pathogen associated molecular patterns. However, during the uptake of OMVs by dendritic cells (DCs), the interaction between lipopolysaccharide and toll-like receptor 4 induces rapid DC maturation and uptake blockage, a phenomenon we refer to as “maturation-induced uptake obstruction” (MUO). Herein we decorated OMV with the DC-targeting αDEC205 antibody (OMV-DEC), which endowed the nanovaccine with an uptake mechanism termed as “not restricted to maturation via antibody modifying” (Normandy), thereby overcoming the MUO phenomenon. We also proved the applicability of this nanovaccine in identifying the human tumor neoantigens through rapid antigen display. In summary, this engineered OMV represents a powerful nanocarrier for personalized cancer vaccines, and this antibody modification strategy provides a reference to remodel the DC uptake pattern in nanocarrier design.
Antibiotic therapy is one of the most important approaches against bacterial infections. However, the improper use of antibiotics and the emergence of drug resistance have compromised the efficacy of traditional antibiotic therapy. In this regard, it is of great importance and significance to develop more potent antimicrobial therapies, including the development of functionalized antibiotics delivery systems and antibiotics-independent antimicrobial agents. Outer membrane vesicles (OMVs), secreted by Gram-negative bacteria and with similar structure to cell-derived exosomes, are natural functional nanomaterials and known to play important roles in many bacterial life events, such as communication, biofilm formation and pathogenesis. Recently, more and more reports have demonstrated the use of OMVs as either active antibacterial agents or antibiotics delivery carriers, implying the great potentials of OMVs in antibacterial therapy. Herein, we aim to provide a comprehensive understanding of OMV and its antibacterial applications, including its biogenesis, biofunctions, isolation, purification and its potentials in killing bacteria, delivering antibiotics and developing vaccine or immunoadjuvants. In addition, the concerns in clinical use of OMVs and the possible solutions are discussed.
Statement of significance
The emergence of antibiotic-resistant bacteria has led to the failure of traditional antibiotic therapy, and thus become a big threat to human beings. In this regard, developing more potent antibacterial approaches is of great importance and significance. Recently, bacterial outer membrane vesicles (OMVs), which are natural functional nanomaterials secreted by Gram-negative bacteria, have been used as active agents, drug carriers and vaccine adjuvant for antibacterial therapy. This review provides a comprehensive understanding of OMVs and summarizes the recent progress of OMVs in antibacterial applications. The concerns of OMVs in clinical use and the possible solutions are also discussed. As such, this review may guide the future works in antibacterial OMVs and appeal to both scientists and clinicians.
Challenges to effective delivery of drugs following oral administration has attracted growing interest over recent decades. Small molecule drugs (<1000 Da) are generally absorbed across the gastrointestinal tract into the portal blood and further transported to the systemic circulation via the liver. This can result in a significant reduction to the oral bioavailability of drugs that are metabolically labile and ultimately lead to ineffective exposure and treatment. Targeting drug delivery to the intestinal lymphatics is attracting increased attention as an alternative route of drug transportation providing multiple benefits. These include bypassing hepatic first-pass metabolism and selectively targeting disease reservoirs residing within the lymphatic system. The particular physicochemical requirements for drugs to be able to access the lymphatics after oral delivery include high lipophilicity (logP>5) and high long-chain triglyceride solubility (> 50 mg/g), properties required to enable drug association with the lipoprotein transport pathway. The majority of small molecule drugs, however, are not this lipophilic and therefore not substantially transported via the intestinal lymph. This has contributed to a growing body of investigation into prodrug approaches to deliver drugs to the lymphatic system by chemical manipulation. Optimised lipophilic prodrugs have the potential to increase lymphatic transport thereby improving oral pharmacokinetics via a reduction in first pass metabolism and may also target of disease-specific reservoirs within the lymphatics. This may provide advantages for current pharmacotherapy approaches for a wide array of pathological conditions, e.g. immune disease, cancer and metabolic disease, and also presents a promising approach for advanced vaccination strategies.
In this review, specific emphasis is placed on medicinal chemistry strategies that have been successfully employed to design lipophilic prodrugs to deliberately enable lymphatic transport. Recent progress and opportunities in medicinal chemistry and drug delivery that enable new platforms for efficacious and safe delivery of drugs are critically evaluated.
Aldehyde dehydrogenase (ALDH), a cancer stem cell biomarker, is related to drug resistance. Co-treatment of anti-cancer drug (CPT) and ALDH inhibitor (DEAB) can overcome the drug resistance of cancer stem cells (CSCs) and finally cure cancers without relapse. We herein introduce a prodrug (DE-CPT) - consisting of 1,3-oxathiolane as an ROS responsive scaffold, and an aldehyde protecting group of DEAB - to deliver the CPT and DEAB upon reaction with ROS. From tests of the sphere-forming ability and CSC marker subpopulation, we found that DE-CPT efficiently decreases the CSCs population and kills the cancer cells.
Although cancer immunotherapy has taken center stage in mainstream oncology inducing complete and long-lasting tumor regression, only a subset of patients receiving treatment respond and others relapse after an initial response. Different tumor types respond differently, and even in cancer types that respond (hot tumors), we still observe tumors that are unresponsive (cold tumors), suggesting the presence of resistance. Hence, the development of intrinsic or acquired resistance is a big challenge for the cancer immunotherapy field. Resistance to immunotherapy, including checkpoint inhibitors, CAR-T cell therapy, oncolytic viruses, and recombinant cytokines arises due to cancer cells employing several mechanisms to evade immunosurveillance.
Soon after its discovery in 2004, Graphene gained a lot of attention in the scientific community and thus, has been broadly investigated due to its unique features and immense applications in the field of nanomedicine, bio-imaging, bio-sensors, drug delivery, biomedical applications, and pharmaceuticals. Graphene is a single layered, two-dimensional carbon molecule having a hexagonal packed structure arranged in a honey-comb cross section manner. Graphene and its derivatives such as graphene oxide (GO), graphene quantum dots (GQDs), and mono-layer and bi-layer graphene are vastly investigated for their scientific applications. Among different applications to date, graphene was successfully used for the first time as a drug delivery vehicle for cancer chemotherapy in 2008. Since then, graphene and graphene-based nanomaterials were massively studied for their application in drug and gene delivery, cancer treatment, and cancer diagnosis due to their unique physicochemical Properties.
This chapter explores the basic knowledge about the history, chemistry, and types of graphene with a spotlight on the preparation, characterization, and functionalization of graphene oxide nanoparticles. Moreover, due to the ample use of graphene oxide nanomaterials in the biomedical field, we also discussed its application in cancer therapy and cancer diagnosis. Furthermore, this chapter also highlights the future perspectives of graphene and graphene-based nanoparticles.