What this is
- This review examines the impact of tumor-derived metabolites on T cell function within the ().
- It discusses how these metabolites, including lactate, lipids, and amino acids, can either suppress or enhance T cell-mediated immunity.
- The review proposes therapeutic strategies targeting metabolic pathways to improve the efficacy of T cell-based immunotherapies.
Essence
- Tumor-derived metabolites significantly influence T cell functionality, either promoting or inhibiting anti-tumor immune responses. Targeting these metabolic pathways offers potential strategies to enhance immunotherapy outcomes.
Key takeaways
- Tumor cell metabolism alters the , impacting T cell efficacy. For example, lactate accumulation can create an acidic environment that inhibits T cell activity, while optimal lactate levels may enhance T cell function.
- Cholesterol and amino acid metabolism also play crucial roles in T cell suppression. Elevated cholesterol levels can lead to T cell exhaustion, while amino acid metabolites like kynurenine can impair T cell activation.
- Innovative therapeutic strategies targeting these metabolites could restore T cell function and improve the effectiveness of cancer immunotherapies, highlighting the need for precise modulation of metabolite levels.
Caveats
- The review emphasizes the complexity of metabolite interactions, suggesting that indiscriminate reduction of certain metabolites could impair T cell responses rather than enhance them.
- The full spectrum of metabolites influencing T cell function remains largely undefined, indicating a need for further research to identify and target these compounds effectively.
Definitions
- tumor microenvironment (TME): The environment surrounding a tumor, including various cell types, extracellular matrix, and biochemical signals that influence tumor behavior and immune responses.
- Warburg effect: A metabolic phenomenon where cancer cells preferentially produce energy through glycolysis followed by lactic acid fermentation, even in the presence of sufficient oxygen.
AI simplified
Facts
Abnormal tumor metabolism is a crucial hallmark of cancer, influencing disease progression and prognosis. Metabolites derived from tumor cells critically mediate immune cell function. Tumor cell-derived metabolites can reshape the tumor microenvironment, subsequently affecting the therapeutic outcomes of immunotherapy.
Open questions
How do specific tumor cell-derived metabolites modulate the anti-tumor immune response or create immune suppressive microenvironments, particularly across various types of cancer and at different stages of disease? Can specific tumor cell-derived metabolites be precisely targeted to selectively enhance the effector function of T cells and other immune cells within the tumor microenvironment? How do tumor cell-derived metabolites interact with immune checkpoint pathways, and can these interactions be exploited to enhance the efficacy of checkpoint inhibitors?
Introduction
One prominent feature of tumor cell metabolism is the Warburg effect, where aerobic glycolysis leads to the accumulation of lactate. This accumulation decreases the pH of the surrounding environment, which can disrupt signal transduction involved in immune processes, thereby attenuating the anti-tumor capabilities of T cells [6, 7]. Furthermore, cancer cells’ altered lipid metabolism results in a high concentration of cholesterol within the TME. Elevated cholesterol levels can impair the cytotoxic activity of CD8+ T cells [8]. Notably, tumor cells also consume large quantities of amino acids, including glutamine, arginine, glycine, and serine. The metabolism of these amino acids generates a plethora of toxic byproducts [9, 10]. For instance, the metabolism of glutamine and tryptophan results in the production of γ-aminobutyric acid (GABA) and kynurenine, respectively. Both GABA and kynurenine have been shown to markedly inhibit the proliferation and anti-tumor activities of infiltrating CD8+ T cells [11, 12]. These metabolic interactions within the TME highlight the dual role of T cells: as key players in mounting an immune response against tumors and as victims of the suppressive conditions created by tumor cell-derived metabolites. Understanding these dynamics is essential for developing strategies to enhance the efficacy of immune-based therapies in oncology.
In recent years, there has been an increasing understanding of tumor cell-derived metabolites and their unique contributions to the TME’s complex ecosystem, as well as their roles in tumor progression and immune suppression. Our review systematically and critically summarizes recent findings on the impact of tumor cell-derived metabolites on T cell activities, providing a comprehensive resource for the field. Additionally, we detail the metabolic adaptations of tumor cells within the TME, offering insights into how these changes affect T cell function. Moreover, we discuss future research directions and therapeutic strategies that specifically target these metabolites to enhance the efficacy of immunotherapies.
Tumor microenvironment and dangerous metabolites. The hypermetabolic tumor microenvironment (TME) generates a range of deleterious metabolites, including lactic acid, cholesterol, spermidine,-kynurenines, and adenosine, which play a critical role in modulating the dual functions of immune cells in tumor progression and suppression. l
Overview of T cell generation and differentiation
T lymphocyte maturation process. Hematopoietic stem cells in the bone marrow give rise to T lymphocytes, which migrate to the thymus for maturation. In the thymic cortex, DN T cell precursors, lacking CD4 and CD8 markers, undergo TCR gene rearrangement to generate a diverse TCR repertoire. They then progress to the DP stage, expressing both CD4 and CD8, and move to the thymic medulla for positive and negative selection. This selection ensures self-tolerance and functional competence, resulting in mature SP T cells. These mature T cells exit the thymus and populate peripheral lymphoid tissues, ready to respond to antigens presented by APCs via MHC–TCR interactions.
Metabolic adaptations of tumor cells in the TME
Cancer cells reprogram lipid metabolism to support rapid cell division and to construct new cellular membranes [26]. Lipid reprogramming in cancer includes increased fatty acid synthesis, uptake, and altered lipid signaling, which together contribute to tumor growth and survival [27]. Key enzymes like acetyl-CoA carboxylase (ACC) and fatty acid synthase (FASN) are upregulated, driving de novo synthesis of fatty acids (Fig. 3). Additionally, the excessive production of cholesterol and fatty acids is not only crucial for membrane biogenesis but also modulates signaling pathways that regulate proliferation, apoptosis, and metastasis [28–32]. For instance, increased cholesterol levels suppress miR-33a and SREBP2 mRNA expression, enhance PIM3 expression, and consequently stimulate CRC cell proliferation, accelerate cell cycle progression, and inhibit apoptosis [33]. Notably, cholesterol-rich lipid rafts serve as platforms for receptor-mediated signaling, enhancing oncogenic signaling pathways. Squalene epoxidase mediates cisplatin resistance through a cholesterol-dependent pathway that stabilizes c-Myc via lipid raft-localized Akt [34].
Cancer cells exhibit an increased demand for amino acids, not only for protein synthesis but also to support anabolic metabolism and redox balance [35]. Glutamine, in particular, is vital for cancer cells, serving multiple roles: it fuels the TCA cycle, supports nucleotide synthesis, and acts as a nitrogen donor for other biosynthetic processes [36–38]. Amino acids like serine and glycine are also pivotal, contributing to one-carbon metabolism, which is essential for nucleotide synthesis and methylation reactions necessary for DNA replication and repair [39]. Targeting amino acid metabolic pathways, therefore, presents a strategy to inhibit the supplies essential for tumor growth (Fig. 3). For instance, the glutamine antagonist prodrug DRP-104 significantly impairs the growth of KEAP1 mutant lung tumors by inhibiting glutamine-dependent nucleotide synthesis and enhancing anti-tumor T cell responses [40]. Similarly, glioblastoma excrete large amounts of branched-chain ketoacids (BCKAs) via monocarboxylate transporter 1. These excreted BCKAs suppress the phagocytic activity of tumor-associated macrophages, thereby contributing to tumor immune evasion [41].
The high rate of proliferation in cancer cells requires an ample supply of nucleotides for DNA and RNA synthesis [35]. Enhanced nucleotide metabolism ensures the availability of purines and pyrimidines, which are synthesized through both de novo and salvage pathways [42]. Given their critical role in DNA replication, enzymes involved in nucleotide synthesis are targeted by many chemotherapeutic agents, aiming to disrupt the proliferation of rapidly dividing tumor cells. For instance, targeting CSN6 decreases de novo nucleotide synthesis, increases chemosensitivity, and, when combined with butyrate treatment, improves chemotherapy efficacy [43]. Additionally, thymidylate synthase (TS) is intricately linked with EMT in cancer cells, showing elevated levels in mesenchymal-like cells. Targeting TS could reduce EMT traits and improve therapeutic outcomes [44] (Fig. 3).
Metabolic processes in tumor cells. Cancer cells uptake glucose, fatty acids, and amino acids from the extracellular environment. Glucose is metabolized into lactate via glycolysis, which is excreted into the TME. Lipid metabolism is connected to the TCA cycle through the production of acetyl-CoA, which serves as a precursor for fatty acid synthesis. Amino acids, such as glutamine, contribute both to TCA cycle intermediates for energy production and to nitrogen metabolism, supporting various biosynthetic processes.
Metabolic influence of tumor cells on T cell dynamics
The effects of tumor cell-derived lactate on T cells
In many cancers, tumor cells exhibit a high glycolytic rate, resulting in substantial lactate production and accumulation in the TME. This elevated lactate not only contributes to the acidic nature of the TME, but also has significant immunosuppressive effects on infiltrating T cells [45, 46]. Solute carrier family 16 member 3 (SLC16A3) encodes monocarboxylate transporter 4 (MCT4), responsible for exporting lactate and other monocarboxylates. High glycolytic activity in tumor cells leads to increased lactate production, and the transport of lactate mediated by SLC16A3 contributes to an immunosuppressive microenvironment, reducing the efficacy of immune checkpoint inhibitors by impairing CD8+ T cell function. Inhibiting SLC16A3 suppresses glycolysis and lactate efflux, thereby enhancing T cell-mediated tumor responses and improving outcomes with anti-PD-1 therapy. This identifies SLC16A3 as a promising target for overcoming resistance to immunotherapy in cancer [47]. Similarly, in glioblastoma, elevated lactate levels within the TME impede CD8+ T cell migration and infiltration, contributing to immune suppression. Through bulk and single-cell RNA-seq analyses, alongside machine learning and cell-cell interaction studies, these findings clarify how lactate modifies the immune landscape of glioblastoma [48]. Importantly, tumor-derived lactate impairs CD8+ T cell cytotoxicity by inhibiting pyruvate carboxylase and disrupting the TCA cycle, specifically anaplerosis. Targeting pyruvate dehydrogenase restores T cell metabolic functions, promoting succinate secretion and activating the succinate receptor, thereby maintaining T cell cytotoxicity in a lactate-rich TME [49]. This reveals pyruvate dehydrogenase as a critical therapeutic target to enhance T cell function in cancer treatment.
Interestingly, advanced materials have also been harnessed to rescue lactate metabolism, thereby reversing T cell suppression and boosting immunotherapy outcomes. For instance, material-engineered catalysts targeting intratumoral lactate enhance immunotherapy by catalytically depleting lactate, inducing metabolic reprogramming and apoptosis in tumor cells. This shift reduces glucose availability and induces mitochondrial damage, effectively activating M1-polarized macrophages and CD8+ T cells, thereby boosting anti-tumor immunity [60]. Interestingly, a novel tumor-specific peroxynitrite nanogenerator, APAP-P-NO, selectively disrupts metabolic homeostasis in melanoma cells, leading to significant changes in key metabolites. This disruption reduces lactate production and modifies the TCA cycle, effectively reversing the immunosuppressive TME. Consequently, there is an enhanced anti-tumor immune response, characterized by macrophage polarization, reduced suppressor cell populations, and restored CD8+ T cell infiltration, thereby increasing the efficacy of immunotherapies like anti-PD-L1 without causing systemic toxicities [61]. Importantly, a novel nanoplatform combining hydroxycamptothecin and siMCT-4 effectively targets lactate metabolism in tumor cells, inhibiting lactate efflux and inducing apoptosis. This intervention shifts tumor-associated macrophages from an M2 to an M1 phenotype, reactivating CD8+ T cell function and transforming an immunosuppressive TME into an immunoreactive one. This strategy enhances tumor immunotherapy, significantly reducing tumor growth and lung metastasis in vivo, and offers a potent approach to convert “cold” tumors into “hot” tumors [62].
Lactate seems to exhibit a dual role in promoting anti-tumor immunity. This paradox highlights the critical importance of precisely regulating lactate levels within the TME. While excessive lactate can inhibit immune responses, optimal levels can enhance the stemness and efficacy of CD8+ T cells through metabolic and epigenetic modifications. For instance, administration of sodium lactate in mice has been shown to increase the population of stem-like TCF-1-expressing CD8+ T cells within tumors, leading to significant inhibition of tumor growth. This finding suggests that a balanced approach to managing lactate concentrations could be crucial [63]. Reducing lactate excessively might diminish these beneficial effects on CD8+ T cell function, underscoring the need for precise modulation of lactate to harness its potential in enhancing anti-tumor immune responses. Thus, developing strategies that finely tune the lactate levels could provide a more effective means of controlling tumor progression and improving the outcomes of immunotherapies.
Effects of lactic acid produced by tumor cell metabolism on T lymphocytes. Lactate impairs CD8T cell cytotoxicity by inhibiting pyruvate carboxylase and disrupting the TCA cycle; MCT1 uptake of lactate enhances Treg cell function through NFAT1 nuclear translocation-mediated upregulation of PD-1 expression; and lactate induces apoptosis of naïve T cells by disrupting autophagy, mitochondrial hyperactivation, and increasing reactive oxygen species by inhibiting FIP200 expression. +
| Compounds | Mechanisms | T cell functional effects | Impacts on tumor | Ref |
|---|---|---|---|---|
| Lithium | Block lysosomal acidification Rescue lysosomal diacylglycerol–PKCθ signaling Localize MCT1 to the mitochondrial membrane | Attenuate lactate-induced CD8T cell immunosuppression+Improve T cell energy utilization | Improve tumor immunosuppression | [] [57] |
| Dichloroacetate | Inhibit macrophage ARG1 expression Inhibit IL-23/IL-17 pathway Reduce lactic acid production | Enhance T cell response | Promote anti-tumor immunotherapy | [,] [58] [59] |
| Dimethyl fumarate | Inhibit GAPDH | Enhance TIL anti-tumor response | Inhibit tumor growth | [] [60] |
| Switch-2 | Bind to IL-2 receptor subunit IL-2Rα Trigger STAT5 activation | Activate CD8T cells+ | Enhance anti-tumor response | [] [61] |
| Gd/CeO2 | Oxidize lactic acid; generate -OH Induce mitochondrial damage | Activate CD8T cells+ | Enhance anti-tumor immunity | [] [62] |
| APAP-P-NO | Produce large quantities of nitrite S-nitrosylation impair GAPDH activity | Reduce Treg cellsPromote CD8T cells infiltration+ | Reverse immunosuppression TME | [] [63] |
| HMONs@HCPT-BSA-PEI-CDM-PEG@siMCT-4 | Inhibit lactate efflux | Restore T cell activity | Inhibit tumor growth and metastasis | [] [64] |
| Sodium lactate | Inhibit histone deacetylase in CD8T cells+ | Increase TCF-1 expression | Promote cancer immunotherapy | [] [65] |
The effects of tumor cell-derived lipid-related metabolites on T cells
X-box binding protein (XBP) is a transcription factor crucial for the unfolded protein response. During endoplasmic reticulum (ER) stress, XBP1 mRNA is spliced by inositol-requiring enzyme 1, producing the active XBP1s form, which regulates genes involved in restoring ER function and managing cellular stress [68]. Cholesterol in the TME triggers exhaustion in CD8+ T cells by inducing expression of immune checkpoints like PD-1 and 2B4, mediated through increased ER stress and activation of the XBP1 (Fig. 5D). Reducing cholesterol levels or inhibiting XBP1 in these T cells restores their anti-tumor activity, uncovering a metabolic mechanism for T cell exhaustion and presenting a novel approach to enhance the efficacy of T cell-based immunotherapies [8]. In addition, loss of cholesterol 25-hydroxylase (CH25H) in pancreatic ductal adenocarcinoma (PDAC) enhances cholesterol accumulation, promoting tumor progression and reducing CD8+ T cell infiltration by facilitating autophagy and downregulating MHC-I (Fig. 5E). Reintroduction of CH25H decreases PDAC cell viability under cholesterol scarcity and slows tumor growth, particularly when combined with immune checkpoint inhibitors, highlighting CH25H as a potential target for enhancing immunotherapy efficacy in PDAC [69]. Moreover, cancer-derived cholesterol sulfate inhibits DOCK2, a critical activator for T cell migration and activation, thereby preventing T cell infiltration into tumors [70] (Fig. 5F). Notably, a matrix metalloproteinase-2-sensitive nanovesicle is developed to enhance photodynamic cancer immunotherapy by targeting cholesterol metabolism in CD8+ T cells and tumor cells within the TME. This intervention reinvigorates T cell function and inhibits tumor cell migration, amplifying the immune response and significantly enhancing tumor growth suppression in a B16-F10 mouse model. This strategy offers a novel approach to augment cancer immunotherapy by manipulating cholesterol metabolism [71]. It should be pointed out that intratumoral T cells exhibit cholesterol deficiency, impairing their proliferation and promoting autophagy-mediated apoptosis [72]. Therefore, precise control of cholesterol levels in the TME becomes a potential strategy to optimize T cell functional states, preventing the exhaustion caused by over-activation and the functional suppression due to low cholesterol levels. Through pharmacological intervention or genetic editing techniques to precisely regulate cholesterol metabolism in the TME, it is possible to reactivate and enhance T cell anti-tumor responses, offering a new direction for cancer treatment. This approach must be carefully implemented to ensure that cholesterol levels are appropriately balanced, neither too high nor too low, to maximize the effectiveness of immunotherapy.
The effects of tumor cell-derived lipid-related metabolites on T cells. In NSCLC, KRAS and TP53 mutant ATX and its metabolite LPA reduce CD8T cell infiltration, and the CERS4/Rhob/Tim-3 axis is strongly associated with T cell infiltration.Tumor cells inhibit CD8T cell activation and promote Treg function through 11β-HSD1 activated glucocorticoids.5-LO and its metabolite leukotrienes recruit T cells and dendritic cells via the chemokines CCL20 and CXCL9 to mediates anti-tumor effects.Tumor cell-derived cholesterol triggers CD8T cell depletion by increasing endoplasmic reticulum stress and activation of XBP1 to induce expression of immune checkpoints such as PD-1 and 2B4.CH25H deficiency in PDAC causes cholesterol accumulation, promotes tumor progression, and reduces CD8T cell infiltration.Cancer-derived cholesterol sulfate affects T cell infiltration by inhibiting DOCK2. A B C D E F + + + +
The effects of tumor cell-derived amino acid-related metabolites on T cells
Tumor cell-derived metabolites such as spermidine, glutamate, and kynurenines result from the altered metabolism of amino acids, a process frequently upregulated to support rapid growth and survival under hypoxic conditions. By modulating local concentrations of these metabolites, tumor cells can exert profound immunomodulatory effects, such as inducing T cell exhaustion, impairing cytotoxic activity, and altering T cell metabolism. Understanding how these amino acid-related metabolites influence T cell behavior is crucial for developing strategies that can enhance T cell responsiveness and improve the outcomes of immunotherapies in cancer treatment.
The effects of tumor cell-derived amino acid-related metabolites on T cells. In tumors overexpressing IDO/TDO, the tryptophan metabolite-kynurenine activates the AHR pathway, which enhances the expression of PD-1 on CD8T cells and activates Tregs leading to an increase in IL-10 secretion, thereby promoting chemoresistance via the STAT3/BCL2 pathway.Cancer cells utilize glutamine to produce the neurotransmitter GABA via GAD1 and inhibit CD8T cell infiltration via β-catenin signaling.Elevated levels of the methionine metabolites 5-methylthioadenosine and SAM are associated with T cell depletion in HCC.Metabolite spermine from tumor cells inhibits TCR signaling. A B C D l + +
The effects of tumor cell-derived adenosine on T cells
Adenosine in the TME is primarily sourced from the breakdown of ATP released by stressed or dying tumor cells and immune cells under hypoxic conditions. It impairs T cell proliferation and diminishes tumoricidal activities such as cytotoxicity and key cytokine production, mediated through A3 receptor interaction [78]. Similarly, the senescent TME, enriched in adenosine due to senescent tumor cells stimulating CD73 expression on tumor-associated macrophages via IL-6 and the JAK/STAT3 pathway, impedes anti-tumor immunity [79]. Moreover, blocking the CD39-adenosine pathway restores T cell proliferation and enhances CTL and NK cell cytotoxicity, highlighting a potential immunotherapeutic avenue to counteract tumor-mediated immune evasion [80]. Adenosine accumulation in solid tumors inhibits the motility of CD8+ T cells from HNSCC patients more than those from healthy donors, primarily through primarily through adenosine 2a receptor (A2aR) mediated suppression of KCa3.1 channel activity. A2aR signaling suppresses KCa3.1 channel activity by increasing cAMP levels, which in turn activates PKA, leading to the inhibition of KCa3.1. This reduces T cell motility since KCa3.1 is crucial for regulating ionic balance and membrane potential needed for migration. Activation of KCa3.1 channels with 1-EBIO restores T cell migration, overcoming adenosine’s inhibitory effects [81, 82].
Effects of adenosine in TME on T cell function. Tumor cells with high self-expression of CD39 and CD73, which together convert ATP to adenosine, stimulate CD73 expression on TAM via the IL-6 and JAK/STAT3 pathways, which hydrolyze ATP to adenosine. Adenosine in the TME interferes with T cell proliferation, migration, and infiltration by activating A2aR and inhibiting its mediated KCa3.1 channel activity.
The effects of other tumor cell-derived metabolites on T cells
Tumor-derived d-2-hydroxyglutarate (D2HG), an oncometabolite produced by mutant isocitrate dehydrogenase (IDH), impairs CD8+ T cell function by altering their metabolism through inhibition of LDH. This interaction reduces T cell cytotoxicity and IFN-γ signaling, affecting their anti-tumor efficacy. These findings, corroborated by clinical data from IDH1 mutant glioma patients, underscore d-2HG’s role in modulating immune responses in the TME, suggesting potential therapeutic targets for enhancing T cell activity in cancer [89]. Similarly, D2HG impairs CD8+ T cell and CAR-T cell function by inhibiting expansion and cytokine production. Modifying CAR-T cells with D2HGDH, an enzyme that converts D2HG to 2-oxoglutarate, enhances their anti-tumor activity. Overexpression of D2HGDH in CAR-T cells reduces serum D2HG levels, promotes T cell function, and improves survival in mice with IDH1-mutated NALM6 tumors, highlighting a potential strategy to enhance immunotherapy efficacy by metabolically reprogramming T cells [90].
As a crucial intermediate in the TCA cycle, succinate functions not only in metabolism but also as a signaling molecule that can modulate hypoxic responses in cells and is linked to inflammatory processes. Exposure to high succinate levels, often seen in SDH-deficient tumors like pheochromocytoma and paraganglioma, suppresses human CD4+ and CD8+ T cell activity by inhibiting cytokine secretion and degranulation. This effect is mediated by succinate’s accumulation and uptake via MCT1, which inhibits succinyl coenzyme A synthetase. This inhibition disrupts the TCA cycle, impairing glucose metabolism and consequently suppressing T cell function [91]. Chondroitin synthase 1 (CHSY1) is an enzyme crucial for the biosynthesis of chondroitin sulfate, a key component of the extracellular matrix. It functions by adding sugar residues to chondroitin sulfate chains, contributing to cell signaling, adhesion, and tissue structure [92]. CHSY1 exacerbates colorectal cancer metastatic progression by inducing CD8+ T cell exhaustion via the succinate metabolism pathway. Targeting CHSY1 with artemisinin, in conjunction with anti-PD-1 therapy, significantly reduces colorectal cancer liver metastasis. This dual approach, enhancing T cell function and inhibiting metastatic gene activity, offers a potent strategy for treating colorectal cancer liver metastases [93].
Increased levels of the tumor metabolite 5′-deoxy-5′-methylthioadenosine (MTA), stemming from a deficiency in the enzyme methylthioadenosine phosphorylase (MTAP), suppress T cell proliferation, activation, differentiation, and effector functions through modulation of the Akt pathway and interference with protein methylation. Conversely, in highly activated T cells, MTA exhibits cytotoxic effects. Restoration of MTAP expression in tumor cells enhances T cell proliferative responses, underscoring MTA’s role in tumor-induced immune evasion and its potential as a target for cancer immunotherapy [94]. Notably, PRMT5 inhibitors, such as EPZ015666 and naturally occurring MTA, reduce T cell proliferation, viability, and functionality, impacting essential cellular processes. Inhibition affects T cell metabolism and modulates key signaling pathways like p53 and AKT/mTOR. While targeting PRMT5 presents a therapeutic strategy for MTAP-deficient tumors, these findings highlight the potential immunosuppressive side effects on T cell responses, underscoring the need for careful evaluation of immune system impacts in cancer therapy development [95].
| Metabolite | Mechanisms | T cell functional effects | Treatment | Ref |
|---|---|---|---|---|
| D-2-hydroxyglutarate | Inhibit LDH directly | Reduce cytotoxicity Impair IFN-γ signaling Inhibit T cell expansion Reduce cytokine production | D2HGDH-OE CAR-T cells catabolize and metabolize D2HG to enhance anti-tumor effects | [,] [87] [88] |
| Succinate | Interfere with the TCA cycle Inhibit succinyl coenzyme A synthetase | Downregulate TNF and IFN-γ levels | Artemisinin targeting of CHSY1 significantly reduces liver metastasis in colorectal cancer | [,] [80] [90] |
| 5′-deoxy-5′-methylthioadenosine | Reduce regulation of Akt phosphorylation Interferon methylation | Decrease T cell proliferation, activation, differentiation and effector functions | Enhance PRMT5 activity to enhance T cell anti-tumor immunity | [,] [91] [92] |
| Nicotinamide adenine dinucleotide | NADparticipates in ATP synthesis+Regulate cellular energy metabolism | Enhance T cell tumor removal function | Lenvatinib targets TET2 in HCC to promote NADmetabolism and enhance anti-tumor immunity+ | [] [93] |
Challenges and prospects
Understanding the complex interplay between tumor cell-derived metabolites and T cell function is pivotal for advancing cancer immunotherapy. These metabolites, varying from amino acids to lipids and nucleotides, can significantly alter T cell behavior, affecting their activation, proliferation, and effector functions. It is essential to delve into how these biochemical signals within the TME can suppress or enhance T cell responses. This insight not only sheds light on the intricate mechanisms of immune evasion but also opens new avenues for therapeutic interventions that can modulate these metabolic interactions to bolster T cell efficacy against cancer.
First, understanding the molecular mechanisms by which tumor cell-derived metabolites impact immune responses is crucial for enhancing the efficacy of cancer immunotherapies. The interaction between IL-7 signaling and adenosine-induced immunosuppression provides a clear example. IL-7 enhances the resistance of CD8+ T cells to the immunosuppressive effects of adenosine in solid tumors by promoting T cell accumulation and inhibiting FoxO1, a key transcription factor. By elucidating this pathway, new therapeutic strategies emerge that could simultaneously target the IL-7 and adenosine pathways, potentially reversing T cell suppression and improving cancer treatment outcomes [98]. Respiratory hyperoxia, where tissues are exposed to elevated oxygen levels, alters the TME by disrupting hypoxia, a key factor in tumor growth and immune evasion. This highlights the potential of manipulating environmental factors, such as oxygen, to influence metabolic pathways involved in tumor progression and immune suppression. Notably, by reducing hypoxia-induced adenosine accumulation, hyperoxia reverses A2aR-mediated suppression of immune responses, facilitating the activation and infiltration of tumor-reactive CD8+ T cells. This, in turn, increases pro-inflammatory cytokines and decreases immunosuppressive factors such as TGF-β, enhancing the effectiveness of immunotherapies. Therefore, a detailed understanding of how tumor-derived metabolites and conditions affect immune cells allows for the refinement of therapeutic strategies, ultimately leading to improved patient outcomes in cancer therapy [99, 100].
Second, the precise modulation of metabolite levels within the TME is a critical aspect of developing effective cancer immunotherapies. While it’s well-documented that several tumor-derived metabolites such as lactate and cholesterol can significantly suppress T cell-mediated anti-tumor activity, these metabolites also play essential roles in maintaining normal physiological functions of T cells. Therefore, indiscriminate reduction of these metabolites could paradoxically impair immune responses rather than enhance them, potentially leading to detrimental therapeutic outcomes. In light of these complexities, therapeutic strategies targeting the metabolic aspects of the TME must be finely tuned. For instance, interventions could be designed to selectively inhibit the metabolic pathways in tumor cells that produce immunosuppressive metabolites while sparing or even supporting the same pathways in T cells. Advanced drug delivery systems that target only tumor cells or specifically modulate the metabolite levels in the TME could provide one avenue for achieving this selectivity. Additionally, understanding the specific metabolic requirements and adaptations of different T cell subsets in the TME could lead to more precise interventions that support effector T cells’ functions while inhibiting Tregs or other immunosuppressive cells.
Third, although the impact of certain tumor-derived metabolites on T cell activity, such as lactate and adenosine, is well-established, the full spectrum of metabolites that regulate T cell function remains largely undefined. Numerous unidentified metabolites likely play significant roles within the TME, influencing T cell efficacy and overall immune response. Therefore, there is a critical need for comprehensive exploration and mapping of the tumor metabolome to uncover these hidden players. Advanced technologies like mass spectrometry and metabolomic profiling, coupled with high-throughput screening methods, could provide insights into complex metabolic interactions between tumor cells and T cells. By deciphering these intricate networks, novel therapeutic targets can be identified and strategies can be developed to manipulate these metabolites, thereby enhancing the effectiveness of immunotherapies.
Lastly, developing new metabolic antagonists and integrating nanotechnology in immunotherapies offer promising strategies to enhance CD8+ T cell anti-tumor activity by targeting specific metabolic pathways utilized by tumor cells. Metabolic antagonists such as IDO inhibitors can alleviate local immunosuppression, while nanocarriers can deliver these agents directly to the TME, ensuring targeted action and minimizing side effects. Combining these approaches with checkpoint inhibitors could further potentiate the immune response, creating a comprehensive treatment strategy. Ongoing research should focus on discovering novel targets through advanced genomic and proteomic studies and developing smarter nanotechnology-based delivery systems that respond dynamically to changes within the TME, paving the way for more effective and adaptive cancer immunotherapies.
Conclusions
The intricate interplay between tumor cell-derived metabolites and T cell functionality in the TME underscores a significant yet complex landscape of immune modulation and metabolic interactions. These metabolites emerge not merely as byproducts of tumor metabolism but as potent regulators of both immune suppression and activation. Their profound impact on the efficacy of immunotherapies highlights crucial avenues for therapeutic intervention. Future strategies that target these metabolic pathways could transform the approach to immunotherapy, enhancing both precision and efficacy of cancer treatments. Achieving this will require a sophisticated understanding of the metabolic signatures unique to different tumor types and their corresponding immunological contexts. Integrating metabolic modulation with current immunotherapeutic strategies presents a promising frontier, potentially overcoming current limitations and pioneering a new era of metabolic engineering in cancer treatment.