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Immune checkpoint inhibitors (ICIs), Ipilimumab, Nivolumab, Pembrolizumab and Atezolizumab, have been applied in anti-tumor therapy and demonstrated exciting performance compared to conventional treatments. However, the unsatisfactory response rates, high recurrence and adaptive resistance limit their benefits. Metabolic reprogramming appears to be...
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... TCR signaling is activated, the expression of several amino acid transporters [solute carrier family (Slc7a5-Slc3a2), alanine, serine, and cysteine system amino acids transporter 2 (ASCT2)] are enhanced with T cell expansion and effector differentiation by activating mTOR (92). Nevertheless, the deprivation of essential nutrients from tumor cells dampens the function of immune cells ( Table 1). Increasing attentions are focused on targeting reprogramming metabolism of amino acids, including glutamine, serine, glycine, arginine, tryptophan, methionine, cysteine and cystine, with increased clinical antitumor benefits. ...Context 2
... that SREBPs are highly upregulated in various cancers and promote tumor growth (133). Lipid metabolism in tumor-associated immune cells (Table 1) shapes an immunosuppressive TME favorable to tumor progression (Figure 3) (43, 134). A common metabolic alteration in the TME is lipid accumulation, a feature associated with immune dysfunction (135) ...Context 3
... homology 2 SHP2 SH2-containing phosphatase 2 SK sphingosine kinase Slc7a5-Slc3a2 solute carrier family S1P sphingosine-1-phosphate SREBP sterol-regulatory-element-binding proteins STAT3 signal transducer and activator of transcription 3 TAMs tumor-associated macrophages TCA cycle tricarboxylic acid cycle TCR T cell receptor TH1 T helper 1 TIGIT T cell immunoreceptor with immunoglobulin and ITIM domains TILs tumor infiltrating lymphocytes TIM-3 T cell immunoglobulin mucin-3 TLR toll like receptor TMB tumor mutation burden TME tumor microenvironment TNBC triple negative breast cancer TNF-a tumor necrosis factor-aTregs, regulatory T cell Trms Tissue-resident memory T cells XBP1 X-box binding protein 1 x-transporter cystine-glutamate exchange ...Citations
... Furthermore, the histological evaluation of ChREBP activation status, that is, its nucleo/cytoplasmic distribution in tumoral and surrounding nontumoral tissues, may be of prognostic value and even inform on the potential sensitivity or resistance to multikinase inhibitor-based therapies. Metabolic reprogramming in tumor cells helps them to escape from immune surveillance by affecting the activation and cytotoxic functions of tumor-associated immune cells [15]. Whether ChREBP-mediated metabolic rewiring might favor the establishment of immune-suppressive conditions is indeed worth exploring. ...
Rewiring of cellular metabolism is now fully recognized as a hallmark of cancer. Tumor cells reprogram metabolic pathways to meet the energetic and macromolecular demands to support unrestricted growth and survival under unfavorable conditions. It is becoming apparent that these adaptations underpin most of the traits that define a cancer cell's identity, including the ability to avoid immune surveillance, endure nutrient and oxygen restrictions, detach and migrate from their natural histological niche, and avert human‐made aggressions (i.e., therapy). In a recent study, Benichou and collaborators identify carbohydrate‐responsive element‐binding protein (ChREBP), a master regulator of physiological glucose metabolism, as an oncogene in hepatocellular carcinoma (HCC) development. Upregulation of ChREBP expression results in a self‐stimulatory loop interconnecting PI3K/AKT signaling and glucose metabolism to feed fatty acid and nucleotide synthesis supporting tumorigenesis. Importantly, pharmacological inhibition of ChREBP activity quells in vivo HCC tumor growth without causing systemic toxicity. This study identifies novel oncometabolic pathways and open up new avenues to improve the treatment of a deadly tumor.
... Given the observed link between T cell exhaustion and poor clinical outcomes in HCC, it is imperative to identify the factors that induce T cell exhaustion in HCC. As tumor progression is a dynamic process involving continuous interactions of tumor cells and other cells in TME including immune cells and stromal cells, tumor cells may profoundly influence various cell types within the tumor ecosystem to promote their survival and the dissemination of malignancy (44,45). Numerous studies have indicated that metabolic changes in tumor cells can directly affect the composition and function of immune cells residing in the same microenvironment (46,47). ...
Hepatocellular carcinoma (HCC) is a leading cause of cancer-related mortality worldwide, ranking fourth in frequency. The relationship between metabolic reprogramming and immune infiltration has been identified as having a crucial impact on HCC progression. However, a deeper understanding of the interplay between the immune system and metabolism in the HCC microenvironment is required. In this study, we used a proteomic dataset to identify three immune subtypes (IM1-IM3) in HCC, each of which has distinctive clinical, immune, and metabolic characteristics. Among these subtypes, IM3 was found to have the poorest prognosis, with the highest levels of immune infiltration and T-cell exhaustion. Furthermore, IM3 showed elevated glycolysis and reduced bile acid metabolism, which was strongly correlated with CD8 T cell exhaustion and regulatory T cell accumulation. Our study presents the proteomic immune stratification of HCC, revealing the possible link between immune cells and reprogramming of HCC glycolysis and bile acid metabolism, which may be a viable therapeutic strategy to improve HCC immunotherapy.
... The ability of cancer cells to modify their metabolism to meet the increased energy demand caused by continuous growth, fast multiplication, and other traits distinctive to neoplastic cells is known as metabolic reprogramming [7]. Metabolic reprogramming is a major obstacle to cancer therapy because metabolite deprivation therapy not only accelerates the growth of tumors but can cause immune cells to become dysfunctional in the tumor microenvironment [8]. Most cancer cells upregulate glucose and/or glutamate uptake to supply carbon for biosynthesis and cope with energy requirements even in the presence of oxygen (Warburg effect). ...
A chemotherapeutic approach is crucial in malignancy management, which is often challenging due to the development of chemoresistance. Over time, chemo-resistant cancer cells rapidly repopulate and metastasize, increasing the recurrence rate in cancer patients. Targeting these destined cancer cells is more troublesome for clinicians, as they share biology and molecular cross-talks with normal cells. However, the recent insights into the metabolic profiles of chemo-resistant cancer cells surprisingly illustrated the activation of distinct pathways compared with chemo-sensitive or primary cancer cells. These distinct metabolic dynamics are vital and contribute to the shift from chemo-sensitivity to chemo-resistance in cancer. This review will discuss the important metabolic alterations in cancer cells that lead to drug resistance.
... In addition, different immune cells mainly produce energy in different ways, so the differentiation of immune cell subsets can be affected by diverse metabolic patterns. 157 Interactions between tumor cells and immune cells affect metabolic reprogramming. On the one hand, tumor cells compete to consume nutrients in the immune microenvironment, such as glucose; on the other hand, tumor cells secrete various metabolites, which affect gene expression and signal transduction in tumor cells and reshape the tumor immune microenvironment. ...
... The interaction between tumor cells and immune cells contributes to metabolic competition in the tumor immune microenvironment, which limits the normal metabolism of nutrients and forms an acidic environment, eventually leading to the weakening of the antitumor immune response and the formation of an immunosuppressive microenvironment. 157 ...
Cancer cells characterized by uncontrolled growth and proliferation require altered metabolic processes to maintain this characteristic. Metabolic reprogramming is a process mediated by various factors, including oncogenes, tumor suppressor genes, changes in growth factors, and tumor-host cell interactions, which help to meet the needs of cancer cell anabolism and promote tumor development. Metabolic reprogramming in tumor cells is dynamically variable, depending on the tumor type and microenvironment, and reprogramming involves multiple metabolic pathways. These metabolic pathways have complex mechanisms and involve the coordination of various signaling molecules, proteins, and enzymes, which increases the resistance of tumor cells to traditional antitumor therapies. With the development of cancer therapies, metabolic reprogramming has been recognized as a new therapeutic target for metabolic changes in tumor cells. Therefore, understanding how multiple metabolic pathways in cancer cells change can provide a reference for the development of new therapies for tumor treatment. Here, we systemically reviewed the metabolic changes and their alteration factors, together with the current tumor regulation treatments and other possible treatments that are still under investigation. Continuous efforts are needed to further explore the mechanism of cancer metabolism reprogramming and corresponding metabolic treatments.
... In this context, hypoxia-induced glycolysis contributes to radioresistance in glioblastoma and platinum resistance in ovarian cancer [29]. Metabolic reprogramming appears to be one key barrier for immunotherapy, which may be associated with the activation of downstream signaling pathways of the immune checkpoints (e.g., PD-1/PD-L1) [30]. Among gynecologic cancers, EC represents a type of malignancy that is the most closely related to metabolic abnormalities, including its pathogenesis, treatment, and prognosis. ...
Cancer cells are usually featured by metabolic adaptations that facilitate their growth, invasion, and metastasis. Thus, reprogramming of intracellular energy metabolism is currently one of the hotspots in the field of cancer research. Whereas aerobic glycolysis (known as the Warburg effect) has long been considered a dominant form of energy metabolism in cancer cells, emerging evidence indicates that other metabolic forms, especially oxidative phosphorylation (OXPHOS), may play a critical role at least in some types of cancer. Of note, women with metabolic syndromes (MetS), including obesity, hyperglycemia, dyslipidemia, and hypertension, have an increased risk of developing endometrial carcinoma (EC), suggesting a close link between metabolism and EC. Interestingly, the metabolic preferences vary among EC cell types, particularly cancer stem cells and chemotherapy-resistant cells. Currently, it is commonly accepted that glycolysis is the main energy provider in EC cells, while OXPHOS is reduced or impaired. Moreover, agents specifically targeting the glycolysis and/or OXPHOS pathways can inhibit tumor cell growth and promote chemosensitization. For example, metformin and weight control not only reduce the incidence of EC but also improve the prognosis of EC patients. In this review, we comprehensively overview the current in-depth understanding of the relationship between metabolism and EC and provide up-to-date insights into the development of novel therapies targeting energy metabolism for auxiliary treatment in combination with chemotherapy for EC, especially those resistant to conventional chemotherapy.
... In this context, hypoxia-induced glycolysis contributes to radioresistance in glioblastoma and platinum resistance in ovarian cancer [29]. Metabolic reprogramming appears to be one key barrier for immunotherapy, which may be associated with the activation of downstream signaling pathways of the immune checkpoints (e.g., PD-1/PD-L1) [30]. Among gynecologic cancers, EC represents a type of malignancy that is the most closely related to metabolic abnormalities, including its pathogenesis, treatment, and prognosis. ...
Poly-ADP-ribose polymerase (PARP) plays an important role in DNA damage detection and repair. PARP inhibitors (PARPi) are a novel class of targeted agents used widely in the treatment of female cancer patients with BRCA mutations, including younger patients. However, the impact of PARPi on ovarian function remains a considerable problem in clinical practice. In this review article, we summarize the current understanding of PARPi's effects on the function of ovary and discuss their potential underlying mechanisms, highlighting the significance of further investigation on the criterion for ovarian failure and its preventive approaches during PARPi treatment.
... However, due to changes in the availability of fuel and other resources within the TME, immunocytes undergo metabolic pattern alterations that have a profound influence on their immune function. Mounting evidence suggests that immunocytes within the TME exist in an altered metabolic state to survive in such a tough environment (6)(7)(8). ...
... The altered lipid metabolism of immunocytes within the TME has raised concerns among the scientific community. Furthermore, a recent study has reported that lipid metabolic alterations in immune cells were commonly associated with the TME and immune dysfunction (6). ...
The tumor microenvironment (TME) has become a major research focus in recent years. The TME differs from the normal extracellular environment in parameters such as nutrient supply, pH value, oxygen content, and metabolite abundance. Such changes may promote the initiation, growth, invasion, and metastasis of tumor cells, in addition to causing the malfunction of tumor-infiltrating immunocytes. As the neoplasm develops and nutrients become scarce, tumor cells transform their metabolic patterns by reprogramming glucose, lipid, and amino acid metabolism in response to various environmental stressors. Research on carcinoma metabolism reprogramming suggests that like tumor cells, immunocytes also switch their metabolic pathways, named “immunometabolism”, a phenomenon that has drawn increasing attention in the academic community. In this review, we focus on the recent progress in the study of lipid metabolism reprogramming in immunocytes within the TME and highlight the potential target molecules, pathways, and genes implicated. In addition, we discuss hypoxia, one of the vital altered components of the TME that partially contribute to the initiation of abnormal lipid metabolism in immune cells. Finally, we present the current immunotherapies that orchestrate a potent antitumor immune response by mediating the lipid metabolism of immunocytes, highlight the lipid metabolism reprogramming capacity of various immunocytes in the TME, and propose promising new strategies for use in cancer therapy.
... In addition, metabolic reprogramming of immune checkpoints is also an effective means to improve drug-resistant and immune microenvironments in the tumour microecosystem. Reprogramming metabolic processes of glucose, lipids, amino acids, nucleotides, and mitochondrial biosynthesis in tumour cells and their altered metabolites contribute to evasion of immune surveillance and elimination [117]. For example, when combined with radiation and temozolomide inhibition of the tumour metabolite D-2Hg in combination with anti-PDL1 immune checkpoint blockade, the median survival J o u r n a l P r e -p r o o f and immune memory of mIDH1 glioma mice improved [118]. ...
Hepatocellular carcinoma (HCC), one of the most common tumours worldwide, is one of the main causes of mortality in cancer patients. There are still numerous problems hindering its early diagnosis, which lead to late patients receiving treatment, and these problems need to be solved urgently. The tumour microecosystem is a complex network system comprising seven parts: the hypoxia niche, immune microenvironment, metabolic microenvironment, acidic niche, innervated niche, mechanical microenvironment, and microbial microenvironment. Intercellular communication is divided into direct contact and indirect communication. Direct contact communication includes gap junctions, tunneling nanotubes, and receptor-ligand interactions, whereas indirect communication includes exosomes, apoptotic vesicles, and soluble factors. Mechanical communication and cytoplasmic exchange are further means of intercellular communication. Intercellular communication mediates the crosstalk between the tumour microecosystem and the host as well as that between cells and cell-free components in the tumour microecosystem, causing changes in the tumour hallmarks of the HCC microecosystem such as changes in tumour proliferation, invasion, apoptosis, angiogenesis, metastasis, inflammatory response, gene mutation, immune escape, metabolic reprogramming, and therapeutic resistance. Here, we review the role of the above-mentioned intercellular communication in the HCC microecosystem and discuss the advantages of targeted intercellular communication in the clinical diagnosis and treatment of HCC. Finally, the current problems and prospects are discussed.
... Along with the rapid development of single cell technologies, heterogeneity of cancer cells within one cancer tissue of a patient can be analyzed and treatment plans considering the diversity and spatial arrangement of the cancer cells can be given. Moreover, the tumor-associated immune cells also have metabolic reprogramming during tumor progression to facilitate the escape of tumor cells from immune surveillance (49,50). Our metabolic tasks analysis method may also be used to uncover the metabolic regulators in the tumor-associated immune cells in future studies. ...
Metabolic reprogramming is one of the hallmarks of tumorigenesis. Understanding the metabolic changes in cancer cells may provide attractive therapeutic targets and new strategies for cancer therapy. The metabolic states are not the same in different cancer types or subtypes, even within the same sample of solid tumors. In order to understand the heterogeneity of cancer cells, we used the Pareto tasks inference method to analyze the metabolic tasks of different cancers, including breast cancer, lung cancer, digestive organ cancer, digestive tract cancer, and reproductive cancer. We found that cancer subtypes haves different propensities toward metabolic tasks, and the biological significance of these metabolic tasks also varies greatly. Normal cells treat metabolic tasks uniformly, while different cancer cells focus on different pathways. We then integrated the metabolic tasks into the multi-objective genome-scale metabolic network model, which shows higher accuracy in the in silico prediction of cell states after gene knockout than the conventional biomass maximization model. The predicted potential single drug targets could potentially turn into biomarkers or drug design targets. We further implemented the multi-objective genome-scale metabolic network model to predict synthetic lethal target pairs of the Basal and Luminal B subtypes of breast cancer. By analyzing the predicted synthetic lethal targets, we found that mitochondrial enzymes are potential targets for drug combinations. Our study quantitatively analyzes the metabolic tasks of cancer and establishes cancer type-specific metabolic models, which opens a new window for the development of specific anti-cancer drugs and provides promising treatment plans for specific cancer subtypes.
