Yuqi Xu1,2†
Peng Li- 1Guangdong Provincial Key Laboratory of Tumor Interventional Diagnosis and Treatment, Zhuhai Institute of Translational Medicine, Zhuhai People’s Hospital Affiliated with Jinan University, Jinan University, Zhuhai, China
- 2The Biomedical Translational Research Institute, Faculty of Medical Science, Jinan University, Guangzhou, China
- 3Department of Geriatrics, The Seventh Affiliated Hospital, Sun Yat-Sen University, Shenzhen, China
- 4Institute of Cell and Gene Technology, Shenzhen University of Advanced Technology, Shenzhen, China
T cells are central mediators of adaptive immunity, playing a pivotal role in eliminating pathogens and tumor cells. In the context of chronic infections and cancer, however, persistent antigenic stimulation drives T cells into a state of exhaustion characterized by diminished effector function, sustained expression of inhibitory receptors, and profound metabolic reprogramming. Emerging evidence indicates that T cell exhaustion is not irreversible and can be alleviated through immune checkpoint blockade, such as targeting PD-1. Moreover, increasing attention has been directed toward the role of intracellular metabolic pathways in shaping T cell fate and function. Strategies aimed at enhancing nutrient availability and metabolic fitness offer an additional avenue to restore T cell activity. This review highlights recent advances in reversing T cell exhaustion through immune checkpoint inhibitors and nutritional interventions, providing novel insights into the precision and personalization of cancer immunotherapy.
1 Introduction
T cells are essential effectors of adaptive immunity and play a critical role in eliminating pathogens and malignant cells. In the setting of chronic infections and cancer, however, persistent antigen exposure drives progressive functional decline, leading to a state known as T cell exhaustion (Tex) (1–4). This dysfunctional state is defined by impaired proliferative capacity, diminished cytokine production, sustained expression of multiple inhibitory receptors, and extensive metabolic reprogramming (5–7). Notably, increasing evidence indicates that exhausted T cells can be functionally reinvigorated through a range of therapeutic strategies, with profound implications for the treatment of chronic infections and cancer (6, 8).
Since Tex is primarily driven by the overexpression of inhibitory receptors, blockade of immune checkpoint receptors represents the predominant strategy to restore T cell function. Immune checkpoint inhibitors (ICIs) can act as potent immune switches, yet their clinical use may be associated with immune-related adverse events (irAEs), particularly when multiple checkpoints are co-targeted (9–14). Moreover, a proportion of patients remains unresponsive to monotherapy with ICIs, underscoring the need for rational combination approaches to enhance therapeutic efficacy.
Beyond immune checkpoint blockade(ICB), novel strategies to reverse T cell exhaustion are rapidly emerging. Within the tumor microenvironment(TME), tumor cells compete with T cells for essential nutrients, thereby restricting T-cell metabolism and accelerating exhaustion. Nutrient supplementation—including amino acids, carbohydrates, fatty acids, and vitamins—has been shown to attenuate the transition of CD8+ T-cell toward terminal exhaustion, thereby augmenting their antitumor activity (15, 16). Notably, increasing evidence suggests that nutritional interventions can synergize with ICIs to enhance therapeutic outcomes and inhibit tumor progression.
Effectively reversing the dysfunctional exhausted phenotype remains critical for optimizing immunotherapeutic strategies. In this review, we summarize current knowledge on the role of ICIs and nutritional interventions in reversing Tex, discuss underlying mechanisms, and highlight key directions for future preclinical and clinical research.
2 Immune checkpoint inhibitors in reversing T cell exhaustion
A hallmark of Tex is the sustained overexpression of inhibitory receptors, including PD-1, T cell immunoglobulin and mucin domain-3 (TIM-3), lymphocyte activation gene-3 (LAG-3), and T cell immunoglobulin and ITIM domain (TIGIT) (17, 18). Under chronic antigenic stimulation, such as in cancer or persistent infection, these immune checkpoints are constitutively expressed on T cells, thereby dampening antitumor immunity (19–21). Immune checkpoint inhibitors can effectively block these inhibitory pathways and restore T cell activity, representing one of the most significant breakthroughs in cancer immunotherapy (22) (Figure 1).
Figure 1. T cell activation versus exhaustion. Acute antigen stimulation promotes full T cell activation, characterized by robust cytotoxic activity, cytokine production, and proliferative capacity. In contrast, persistent antigen exposure during chronic infection or cancer drives effector T cell exhaustion through sustained inhibitory receptor signaling and immunosuppressive cues within the microenvironment.
2.1 Anti-PD-1/anti-PD-L1
Among the inhibitory receptors, PD-1 is the most extensively studied marker of Tex (23, 24). Blockade of the PD-1 pathway partially restores effector function, reduces viral or tumor burden, and has revolutionized immunotherapy (25, 26). PD-1 and its ligands PD-L1 and PD-L2 regulate T cell activation, proliferation, and cytotoxicity in the TME. In particular, PD-1/PD-L1 signaling plays a critical role in establishing and maintaining immune tolerance, thereby restraining antitumor immunity (22).
Monoclonal antibodies targeting PD-1 or PD-L1 have shown remarkable clinical efficacy across multiple cancer types, including melanoma, non-small cell lung cancer (NSCLC), renal cell carcinoma, and bladder cancer (27, 28). Retifanlimab, a humanized anti-PD-1 antibody, has demonstrated durable antitumor activity in melanoma, NSCLC, ulcerative colitis, and Squamous cell carcinoma of the anal canal, supporting its further clinical evaluation in solid tumors (29–31).
Similarly, the anti-PD-L1 antibody atezolizumab improved overall survival (OS) in advanced NSCLC and small cell lung cancer. Furthermore, in the treatment of metastatic colorectal cancer, atezolizumab combined with targeted therapy significantly improved progression-free survival (PFS) and OS (24, 32–34). Collectively, these findings highlight the central role of PD-1/PD-L1 blockade in reinvigorating exhausted T cells.
2.2 Anti-CTLA-4
CTLA-4 attenuates T cell activation by outcompeting CD28 for binding to B7.1 and B7.2 co-ligands (35), thereby suppressing proliferation, IL-2 production, and effector differentiation, and contributing to a protumor immunosuppressive environment (36, 37).
Approved ICIs targeting CTLA-4 include ipilimumab and tremelimumab. Ipilimumab enhances adaptive immune responses to tumor cells by blocking CTLA-4 signaling, but its clinical use is limited by irAEs, such as colitis, thrombocytopenia and ICIs-related hypophysitis (38–40). To achieve safer and more effective therapy, novel strategies aim to preserve CTLA-4 signaling in peripheral tissues while selectively promoting Treg depletion or dysfunction within the TME (41). Thus, CTLA-4 antagonism remains a promising therapeutic approach to enhance antitumor immunity (42).
2.3 Other immune checkpoint inhibitors
Compensatory upregulation of additional inhibitory receptors, including TIM-3, LAG-3, and TIGIT, frequently occurs after PD-1 or CTLA-4 blockade, leading to acquired resistance (43–47).
Preclinical studies have shown that LAG-3 blockade enhances antigen-specific T cell activation and impairs tumor growth, although limited efficacy is observed with monotherapy. By contrast, dual LAG-3/PD-1 blockade produces synergistic antitumor effects (48–50). Similarly, TIM-3 signaling contributes to Tex and apoptosis in cancer, and its blockade restores T cell proliferation and effector function. TIM-3 is often co-expressed with PD-1, marking a more severe exhausted phenotype (51, 52). Combination therapy targeting TIM-3 and PD-1 significantly enhances antitumor activity and has demonstrated tolerability in early-phase clinical trials (53, 54).
TIGIT is also upregulated in multiple malignancies, including melanoma, NSCLC, and acute myeloid leukemia (55–59). By binding to its ligands, TIGIT directly transmits inhibitory signals to T cells. Preclinical evidence supports TIGIT blockade as an effective approach to reinvigorate exhausted T cells and restore antitumor function (60, 61). These findings provide strong rationale for ongoing clinical trials evaluating dual PD-1/TIGIT blockade, as well as combinations with LAG-3 or TIM-3 inhibitors, in cancer patients.
3 Nutritional and metabolic small molecules
Nutrient availability is increasingly recognized as a critical determinant of T cell function (62). Deficiencies in essential nutrients can promote T-cell exhaustion through mechanisms distinct from chronic antigenic stimulation. Conversely, supplementation with macronutrients (e.g., carbohydrates) and micronutrients (e.g., vitamins) has been shown to regulate cancer progression, maintain immune homeostasis, reverse Tex, and enhance antitumor immunity (15). Based on a comprehensive review of the current literature, this study further elucidates how nutritional metabolism influences Tex and modulates ICB therapy (Figure 2).
Figure 2. Nutritional intervention reverses T cell exhaustion and enhances antitumor immunity. Chronic antigen stimulation induces T cells to upregulate immune checkpoint receptors, including PD-1, TIM-3, LAG-3, and TIGIT, which results in progressive loss of effector function and exhaustion. Nutritional interventions with key metabolites—such as D-mannose, galactose, glutamine, linoleic acid, and active vitamin D3 [1α,25(OH)2D3]—can modulate T cell nutrient-sensing pathways and metabolic reprogramming. These interventions act synergistically with immune checkpoint inhibitors to alleviate T cell exhaustion, restore proliferative capacity, cytotoxic activity, and effector cytokine (IFN-γ, TNF-α) production, thereby enhancing T cell–mediated anti-tumor immunity.
3.1 Carbohydrate compounds
As fundamental nutrients, carbohydrates are essential for sustaining T-cell activation, proliferation, and effector activity, with their metabolic utilization profoundly influencing the strength and persistence of immune responses. Numerous studies indicate that supplementing specific carbohydrates can remodel tumor microenvironment metabolism, reverse T-cell exhaustion, and enhance responses to ICB. This represents a promising direction for improving cancer immunotherapy (15, 63, 64).
3.1.1 Glucose
The dependence of tumor cells on aerobic glycolysis may be the most extensively studied metabolic adaptation exploited by tumor cells. As research indicates, tumor cells increase glucose uptake by upregulating glucose transporters such as GLUT1 (65). This leads to glucose deprivation in the tumor-infiltrating lymphocyte microenvironment, impairing T cell function. Studies indicate that GLUT1 overexpressing CAR-T cells enhance T-cell glucose competition, improve antitumor efficacy against hepatocellular carcinoma, and increase CD8+ T-cell survival rates (65–68). Concurrently, numerous investigations are exploring the combination of glucose metabolism modulation with ICIs (69). For instance, short-term supplementation with high-glucose drinks can enhance T-cell-mediated antitumor immune responses against glioblastoma by modulating the gut microbiota, and exhibits synergistic effects with anti-PD-1 immune checkpoint therapy (70).
In addition, Lactic acid is a byproduct of aerobic glycolysis that can acidify the TME, suppress cytotoxic signaling in CD8+ T cells, and upregulate PD-1 expression, thereby enhancing Tex (71–73). Targeting lactate metabolism, such as through monocarboxylate transporter (MCT) inhibitors and LDHA blockers, can alter glycolytic flux in the TME, thereby significantly enhance antitumor immune responses. Furthermore, studies indicate that combining MCT-1 inhibitors with PD-1/PD-L1 blockade therapy can improve the efficacy of ICIs (74–76).
3.1.2 Fructose
High-fructose diets are traditionally associated with metabolic disorders, including type 2 diabetes, cardiovascular disease, and cancer (77). Interestingly, recent studies suggest that dietary fructose can also mitigate CD8+ T cell exhaustion and augment antitumor immunity. In mouse models of melanoma and MC38 adenocarcinoma, a high-fructose diet inhibited tumor growth and prolonged survival. Mechanistically, fructose supplementation reduced the accumulation of terminally exhausted PD-1+TIM-3+ CD8+ T cells and improved effector function within the TME (78). Research findings indicate that GLUT5 CAR-T cells maintain potent antitumor activity across multiple tumor models. Importantly, reduced expression of PD-1 and TIM-3 was detected in tumors infiltrated by GT5 OT-I cells. According to these findings, the adoptive transfer of GT5 T cells can be combined with ICIs to enhance their efficacy. (79).
Fructose also regulates adipocyte metabolism, enhancing antitumor T-cell responses through increased leptin signaling (80). Moreover, gut microbiota can convert fructose into short-chain fatty acids (SCFAs), including acetate and butyrate (81), both of which promote CD8+ T cell antitumor activity (82, 83). These findings suggest that fructose supplementation may enhance CD8+ T cell function via dual mechanisms: elevating adipocyte-derived leptin and increasing microbial-derived SCFAs, thereby attenuating the shift toward terminal exhaustion.
3.1.3 Other carbohydrate compounds
Diminished mannose metabolism is a hallmark of dysfunctional T cells, whereas supplementation with D-mannose restores metabolic programming, preserves stem-like properties through OGT-mediated β-catenin O-GlcNAcylation, and limits exhaustion differentiation. Importantly, D-mannose–expanded T cells retain stemness during long-term culture and exhibit enhanced anti-tumor efficacy, highlighting mannose metabolism as a promising target for cancer immunotherapy (84).
Dietary galactose enhances CD8+ T-cell immunity and suppresses tumor progression by reprogramming hepatocyte metabolism to induce IGFBP-1 production, thereby limiting IGF-1 signaling–dependent T cell exhaustion. Elevated plasma IGFBP-1 levels in cancer patients are associated with reduced Tex and enhanced intratumoral T cell responses, highlighting galactose as a potential dietary strategy to improve cancer immunotherapy (85).
3.2 Amino acids
Amino acids play a central role in orchestrating T-cell metabolism and function. Their metabolic states interact with, and modulate, the utilization of other key nutrients such as glucose and fatty acids, thereby substantially shaping the development of T-cell exhaustion. Within this framework, we highlight amino acids capable of directly mitigating the exhausted T-cell phenotype and exhibiting synergistic effects with ICIs (15, 65, 86).
3.2.1 Glutamine
Glutamine (Gln), the most abundant free amino acid in serum, is essential for cell growth and proliferation (87). Beyond its well-documented role in tumorigenesis and metastasis (88, 89), Gln is critical for immune cell survival and function. Gln depletion impairs lymphocyte proliferation, reduces expression of activation markers and cytokine production, and induces apoptosis (90). In CD8+ T-cell, Gln deprivation not only diminishes effector molecule secretion but also upregulates inhibitory receptors such as PD-1, thereby driving exhaustion (49). Importantly, targeting glutamine metabolism in combination with PD-1/PD-L1 blockade has been shown to restore T-cell function and enhance antitumor immunity, representing a promising therapeutic strategy (69, 91–94).
3.2.2 Taurine
Taurine (Tau) has dual effects in cancer biology, promoting tumor aggressiveness when exploited by malignant cells, yet enhancing CD8+ T cell function when available to immune cells (94–96). Uptake of taurine is mediated by the transporter SLC6A6, which is frequently overexpressed in tumors and correlates with poor prognosis. Tumor-driven taurine competition deprives T cells of this nutrient, leading to apoptosis and functional decline (97). Conversely, taurine supplementation rejuvenates exhausted CD8+ T-cell, reduces apoptosis, and increases IFN-γ and TNF-α secretion. In preclinical models, taurine administration synergized with PD-1 blockade to enhance antitumor activity and reverse Tex (98).
3.2.3 Other amino acids
L-arginine (L-Arg) is an essential amino acid critical for T lymphocyte function. Arginase I/II(ARG1/2) produced by myeloid-derived suppressor cells (MDSCs) increases arginine consumption in the microenvironment, thereby suppressing CD8+ T-cell function and impairing antitumor immunity (99, 100). Inhibiting ARG1/2 within the TME may release T-cell proliferation constraints and activate effective antitumor responses (101, 102). Studies indicate that combining ARG1/2 inhibitors with anti-PD-1 checkpoint inhibitors reshapes the TME, promotes T-cell proliferation, enhances the antitumor efficacy of anti-PD-1 monotherapy, and significantly suppresses tumor growth (101, 103).
Tryptophan deficiency inhibits T lymphocyte proliferation, while indoleamine 2,3-dioxygenase (IDO) inhibitors have been found to activate CD8+ T-cell and reduce PD-1 expression by elevating tryptophan levels (104, 105). Research has found that combining IDO inhibitors with ICIs significantly enhances the antitumor efficacy of ICIs (106–108). Therefore, integrating immunotherapy with targeted amino acid metabolism represents a promising strategy for boosting immunotherapy.
3.3 Fatty acids
As the third essential pillar of immunometabolism, fatty acids function as both energy substrates and signaling molecules, shaping T-cell activation, proliferation, and survival through uptake or de novo synthesis. While dysregulated fatty acid metabolism promotes T-cell exhaustion, emerging evidence indicates that targeted supplementation of specific fatty acids may help restore T-cell function and overcome exhaustion (15, 109).
3.3.1 Trans-vaccenic acid
TVA, a naturally occurring trans fatty acid found in beef, lamb, and dairy products, has been reported to promote tumor infiltration of CD8+ T-cell and enhance their cytotoxicity (110). Mechanistically, TVA inactivates the G protein-coupled receptor GPR43, which normally exerts inhibitory effects on CD8+ T-cell through cAMP suppression (111, 112). By antagonizing GPR43, TVA activates the cAMP–PKA–CREB axis and enhances CD8+ T-cell function. Dietary TVA combined with PD-1 blockade demonstrated synergistic suppression of B16-F10 tumor growth (113).
3.3.2 Linoleic acid
Linoleic acid (LA) has been identified as a positive regulator of cytotoxic T lymphocyte function by promoting mitochondrial fitness and metabolic reprogramming. LA supplementation shifts CD8+ T-cell from an exhausted phenotype toward a memory-like state with enhanced killing capacity. (114). This metabolic adaptation improves tumor control, prevents terminal exhaustion, and augments antitumor responses.
3.4 Vitamin
Vitamins are essential micronutrients required for numerous physiological processes. Unlike macronutrients such as carbohydrates, proteins, and lipids, vitamins do not provide energy but play critical roles in regulating cellular metabolism and immune function. Recent studies increasingly highlight the importance of specific vitamin supplementation in modulating T-cell activity and enhancing antitumor immunity (115, 116).
3.4.1 Vitamin A
All-trans retinoic acid (ATRA), the active metabolite of vitamin A, functions as an agonist of retinoic acid receptors (RARs) to regulate cell growth, differentiation, immunity, and survival (117, 118). Clinical studies indicate that ATRA enhances responses to ICB by reducing immunosuppression, promoting T-cell activity, and improving prognosis across several cancer types (119).
For instance, co-administration of a RARγ agonist with anti–PD-L1 therapy significantly suppressed tumor growth in an immune checkpoint–resistant lung cancer model. This combination enhanced the proliferation of splenic and tumor-infiltrating T cells, thereby augmenting antitumor immunity (120). Furthermore, dual treatment with ATRA and oxaliplatin markedly potentiated anti–PD-1 efficacy in colorectal cancer models by modulating the tumor immune microenvironment and increasing CD8+ T-cell infiltration (119).
3.4.2 Vitamin C
Vitamin C is a crucial micronutrient involved in diverse physiological processes, including immune regulation (115, 121). It has been shown to promote the degradation of PD-L1 protein, thereby reducing its expression and enhancing antitumor immunity (122). Preclinical studies demonstrated that high-dose vitamin C slowed tumor growth in immunocompetent mice. In a lymphoma model, vitamin C synergized with anti–PD-1 therapy, leading to significant tumor inhibition, with some mice achieving complete regression (123). Notably, this combination enhanced CD8+ T-cell infiltration more effectively than either treatment alone, underscoring vitamin C’s potential to strengthen immune checkpoint therapy (124).
3.4.3 Vitamin D
Vitamin D, primarily in its active form 1α,25(OH)2D3, is a fat-soluble vitamin traditionally known for regulating calcium and phosphate homeostasis. Increasing evidence links vitamin D deficiency to elevated risks of cancer and other diseases (125–127), highlighting its therapeutic potential.
Vitamin D can act as an immunoregulatory factor, dampening harmful inflammation while promoting effective antitumor immunity (128). For example, in non-small cell lung cancer patients, 1α,25(OH)2D3/VDR signaling suppressed inhibitory checkpoint receptor expression (e.g., PD-1) on cytotoxic T cells, thereby enhancing their effector function (129, 130). Moreover, maintaining normal vitamin D levels improved outcomes in advanced melanoma patients receiving anti–PD-1 therapy (131). Mechanistically, vitamin D enhances antitumor immunity partly by shaping the gut microbiota, particularly through promoting the growth of Bacteroides fragilis, which synergizes with ICB to inhibit tumor growth (132).
3.4.4 Vitamin B3
Vitamin B3 (nicotinamide and nicotinic acid) is indispensable for cellular metabolism, as it serves as a precursor for nicotinamide adenine dinucleotide (NAD+), a cofactor essential for energy metabolism and T-cell function (133). Declines in NAD+ impair ATP synthesis, disrupt T-cell receptor signaling, and lead to metabolic dysfunction and impaired T-cell activity.
Pharmacological inhibition of NAD+ synthesis, such as via the NAMPT inhibitor FK866, markedly reduces T-cell proliferation and cytokine production (134). Conversely, supplementation with NAD+ precursors such as nicotinamide riboside (NR) attenuates T-cell exhaustion and increases CD4+ and CD8+ T-cell numbers in sepsis mice (135).
Importantly, in preclinical cancer models, NAD+ supplementation enhanced the cytotoxicity of CAR-T cells and synergized with anti–PD-1 therapy. CAR-T cells supplemented with nicotinamide (NAM) demonstrated superior tumor-killing capacity, while anti–PD-1 plus NAM treatment delayed tumor progression and improved therapeutic outcomes (133).
4 Discussion
Prolonged antigen exposure can trap T cells in a dysfunctional state, while tumor cells activate immune checkpoint pathways to suppress antitumor immune responses (6, 7, 136). Clinically, ICIs (e.g., PD-1/PD-L1 inhibitors) have successfully reversed this exhausted phenotype to deactivate tumors (5, 22, 137). However, only a subset of patients achieve durable responses, as cancer cells activate multiple immune escape mechanisms that limit the efficacy of monotherapy (129, 138).
More recently, increasing attention has focused on how nutrients and small-molecule metabolites can modulate immune checkpoint expression, reverse immune exhaustion, and enhance antitumor responses (15). Combination approaches that integrate ICIs with nutrient-based interventions hold promise for broadening the therapeutic benefit to a larger patient population (91, 123). Given that tumor metabolic plasticity occurs in real time, metabolic intervention targeting a single pathway is highly likely to select for pre-existing or newly acquired drug-resistant cell subpopulations within the tumor. These cell subpopulations not only tolerate treatment but may also accelerate proliferation through compensatory pathways (139). More critically, this may inadvertently induce tumor-infiltrating CD8+ T-cell exhaustion, suppress anti-tumor immunity, and promote an immunosuppressive environment. This indirectly provides a sanctuary for cancer stem cells (CSCs), thereby facilitating tumor progression (139–142).
Although it is challenging, we still believe that targeted metabolic intervention in the TME can enhance the anti-tumor immune response. The key lies in dynamically monitoring metabolic changes across different TME cells during treatment and dynamically adjusting metabolic intervention strategies in real time, thereby achieving personalized metabolic tumor immunotherapy. Increasing research indicates that employing isotope tracing (¹³C-glucose/lactate) combined with FDG-PET imaging and magnetic resonance spectroscopy (MRS) to promptly assess tumor metabolism during treatment and adjust metabolic intervention strategies accordingly (140, 143–148).
Additionally, this line of research has offered new insights. By stratifying patients based on cell type-specific metabolic characteristics, it offers a more refined approach to patient segmentation (139). This method holds promise for achieving more personalized and effective cancer treatments, particularly in overcoming drug resistance mechanisms driven by metabolic heterogeneity. Moreover, studies have also revealed cell type–specific nutrient uptake preferences within the TME (149). When designing metabolic interventions, it is important to enhance T cell activation and function by supplying specific nutrients or metabolic modulators, while simultaneously depriving tumor cells and CSCs of key nutrients. This strategy may improve the efficacy of ICIs and strengthen antitumor immunity. Metabolic interventions can also be implemented through cell therapies like GLUT5 CAR-T cells, which precisely target tumor-specific metabolic pathways while avoiding the systemic toxicity associated with metabolic interventions on normal tissues (79).
Looking ahead, the integration of nutritional–metabolic interventions with sensitivity-guided personalized immunotherapy constitutes a key frontier for advancing precise cancer treatment, enhancing clinical efficacy, and reducing therapeutic risks.
Author contributions
YX: Writing – original draft, Writing – review & editing. WY: Writing – original draft, Writing – review & editing. KL: Funding acquisition, Writing – review & editing. PL: Funding acquisition, Writing – review & editing.
Funding
The author(s) declared that financial support was received for this work and/or its publication. This work was supported by the National Natural Science Foundation of China (Grant 32300728 to PL), the Guangdong Basic and Applied Basic Research Foundation (Grant 2022A1515110416 to PL), and Shenzhen Science and Technology Program (JCYJ20240813150420027 to KL).
Conflict of interest
The author(s) declared that this work was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
Generative AI statement
The author(s) declared that generative AI was not used in the creation of this manuscript.
Any alternative text (alt text) provided alongside figures in this article has been generated by Frontiers with the support of artificial intelligence and reasonable efforts have been made to ensure accuracy, including review by the authors wherever possible. If you identify any issues, please contact us.
Publisher’s note
All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.
References
1. Day CL, Kaufmann DE, Kiepiela P, Brown JA, Moodley ES, Reddy S, et al. PD-1 expression on HIV-specific T cells is associated with T-cell exhaustion and disease progression. Nature. (2006) 443:350–4. doi: 10.1038/nature05115
2. Kang TG, Johnson JT, Zebley CC, and Youngblood B. Epigenetic regulation of T cell exhaustion in cancer. Nat Rev Cancer. (2025). doi: 10.1038/s41568-025-00883-y
3. Naulaerts S, Datsi A, Borras DM, Antoranz MA, Messiaen J, Vanmeerbeek I, et al. Multiomics and spatial mapping characterizes human CD8(+) T cell states in cancer. Sci Transl Med. (2023) 15. doi: 10.1126/scitranslmed.add1016
4. Galluzzi L, Smith KN, Liston A, and Garg AD. The diversity of CD8+ T cell dysfunction in cancer and viral infection. Nat Rev Immunol. (2025) 25:662–79. doi: 10.1038/s41577-025-01161-6
6. Sears JD, Waldron KJ, Wei J, and Chang CH. Targeting metabolism to reverse T-cell exhaustion in chronic viral infections. Immunology. (2021) 162:135–44. doi: 10.1111/imm.13238
7. Tang L, Zhang Y, Hu Y, and Mei H. T cell exhaustion and CAR-T immunotherapy in hematological Malignancies. BioMed Res Int. (2021) 2021:6616391. doi: 10.1155/2021/6616391
8. Budimir N, Thomas GD, Dolina JS, and Salek-Ardakani S. Reversing T-cell exhaustion in cancer: lessons learned from PD-1/PD-L1 immune checkpoint blockade. Cancer Immunol Res. (2022) 10:146–53. doi: 10.1158/2326-6066.CIR-21-0515
9. Blum SM, Rouhani SJ, and Sullivan RJ. Effects of immune-related adverse events (irAEs) and their treatment on antitumor immune responses. Immunol Rev. (2023) 318:167–78. doi: 10.1111/imr.13262
10. Naidoo J, Murphy C, Atkins MB, Brahmer JR, Champiat S, Feltquate D, et al. Society for Immunotherapy of Cancer (SITC) consensus definitions for immune checkpoint inhibitor-associated immune-related adverse events (irAEs) terminology. J Immunother Cancer. (2023) 11:e6398. doi: 10.1136/jitc-2022-006398
11. Sano Y, Inoue M, Washino S, Shirotake S, Takeshita H, Miura Y, et al. Clinical outcomes of retreatment or discontinuation after interruption of nivolumab plus ipilimumab due to immune-related adverse events in metastatic renal cell carcinoma patients: A retrospective multicenter study. Urologic Oncol. (2025). doi: 10.1016/j.urolonc.2025.10.021
12. Jiao R, Wang C, Ying H, Nie M, Leng J, Liu Y, et al. Case report of immune checkpoint inhibitor induced cholestatic hepatitis, acute renal injury and asymptomatic pancreatic enzyme elevation simultaneously. Front Immunol. (2025) 16:1679328. doi: 10.3389/fimmu.2025.1679328
13. Chan KK and Bass AR. Autoimmune complications of immunotherapy: pathophysiology and management. BMJ (Clinical Res ed.). (2020) 369:m736. doi: 10.1136/bmj.m736
14. Gu L, Khadaroo PA, Su H, Kong L, Chen L, Wang X, et al. The safety and tolerability of combined immune checkpoint inhibitors (anti-PD-1/PD-L1 plus anti-CTLA-4): a systematic review and meta-analysis. BMC Cancer. (2019) 19:559. doi: 10.1186/s12885-019-5785-z
15. Raynor JL and Chi H. Nutrients: Signal 4 in T cell immunity. J Exp Med. (2024) 221. doi: 10.1084/jem.20221839
16. Zitvogel L, Pietrocola F, and Kroemer G. Nutrition, inflammation and cancer. Nat Immunol. (2017) 18:843–50. doi: 10.1038/ni.3754
17. Pauken KE and Wherry EJ. Overcoming T cell exhaustion in infection and cancer. Trends Immunol. (2015) 36:265–76. doi: 10.1016/j.it.2015.02.008
18. Li C, Yuan Y, Jiang X, and Wang Q. Epigenetic regulation of CD8(+) T cell exhaustion: recent advances and update. Front Immunol. (2025) 16:1700039. doi: 10.3389/fimmu.2025.1700039
19. Goepfert PA, Bansal A, Edwards BH, Ritter JGD, Tellez I, McPherson SA, et al. A significant number of human immunodeficiency virus epitope-specific cytotoxic T lymphocytes detected by tetramer binding do not produce gamma interferon. J Virol. (2000) 74:10249–55. doi: 10.1128/JVI.74.21.10249-10255.2000
20. Reignat S, Webster GJM, Brown D, Ogg GS, King A, Seneviratne SL, et al. Escaping high viral load exhaustion. J Exp Med. (2002) 195:1089–101. doi: 10.1084/jem.20011723
21. Sun Q and Dong C. Regulators of CD8+ T cell exhaustion. Nat Rev Immunol. (2025). doi: 10.1038/s41577-025-01221-x
22. Han Y, Liu D, and Li L. PD-1/PD-L1 pathway: current researches in cancer. Am J Cancer Res. (2020) 10:727–42.
23. Wang Y, Ding Q, and Wei J. Current advances and future directions of combined ICIs and TILs in solid tumors. Cancer Lett. (2025), 218145. doi: 10.1016/j.canlet.2025.218145
24. Kepp O and Kroemer G. FDA approves lurbinectedin in combination with atezolizumab for extensive-stage small cell lung cancer. Oncoimmunology. (2025) 14:2584898. doi: 10.1080/2162402X.2025.2584898
25. Dong X, Yao X, Li R, Li Y, and Li Y. Comparison of efficacy and safety of first-line immunotherapy combined with chemotherapy in extensive-stage small cell lung cancer, a retrospective study. Sci Rep. (2025) 15:40167. doi: 10.1038/s41598-025-23874-3
26. Yan Y, Zhang L, Zuo Y, Qian H, and Liu C. Immune checkpoint blockade in cancer immunotherapy: mechanisms, clinical outcomes, and safety profiles of PD-1/PD-L1 inhibitors. Arch Immunol Ther Exp (Warsz). (2020) 68:36. doi: 10.1007/s00005-020-00601-6
27. Ohaegbulam KC, Assal A, Lazar-Molnar E, Yao Y, and Zang X. Human cancer immunotherapy with antibodies to the PD-1 and PD-L1 pathway. Trends Mol Med. (2015) 21:24–33. doi: 10.1016/j.molmed.2014.10.009
28. Sun Q, Hong Z, Zhang C, Wang L, Han Z, and Ma D. Immune checkpoint therapy for solid tumours: clinical dilemmas and future trends. Signal Transduct Target Ther. (2023) 8:320. doi: 10.1038/s41392-023-01522-4
29. Di Giacomo AM, Schenker M, Medioni J, Mandziuk S, Majem M, Gravis G, et al. A phase II study of retifanlimab, a humanized anti-PD-1 monoclonal antibody, in patients with solid tumors (POD1UM-203). ESMO Open. (2024) 9:102387. doi: 10.1016/j.esmoop.2024.102387
30. Rao S, Samalin-Scalzi E, Evesque L, Ben Abdelghani M, Morano F, Roy A, et al. Retifanlimab with carboplatin and paclitaxel for locally recurrent or metastatic squamous cell carcinoma of the anal canal (POD1UM-303/InterAACT-2): a global, phase 3 randomised controlled trial. Lancet (British edition). (2025) 405:2144–52. doi: 10.1016/S0140-6736(25)00631-2
31. Lu S, Vynnychenko O, Kulyaba Y, Kuchava V, Ibrahim A, Moiseenko F, et al. Retifanlimab versus placebo in combination with platinum-based chemotherapy in patients with first-line non-squamous or squamous metastatic non-small-cell lung cancer (POD1UM-304): a phase 3, multiregional, placebo-controlled, double-blind, randomised study. Lancet Respir Med. (2025). doi: 10.1016/S2213-2600(25)00209-7
32. Fehrenbacher LD, Spira AM, Ballinger MP, Kowanetz MP, Vansteenkiste JP, Mazieres JP, et al. Atezolizumab versus docetaxel for patients with previously treated non-small-cell lung cancer (POPLAR): a multicentre, open-label, phase 2 randomised controlled trial. Lancet (British edition). (2016) 387:1837–46. doi: 10.1016/S0140-6736(16)00587-0
33. Huo L, Yue H, Yang R, Sun X, Wang Z, Liu H, et al. Efficacy and safety of first-line targeted and immunotherapy for metastatic colorectal cancer: a network meta-analysis. Front Immunol. (2025) 16:1643133. doi: 10.3389/fimmu.2025.1643133
34. Batah H, Zabor EC, Adcock B, Lee M, Patel P, Patel M, et al. Long-term outcomes of Extensive-Stage small cell lung cancer treated with chemotherapy or Chemo-immunotherapy: A propensity score adjusted cohort study. Lung Cancer. (2025) 210:108847. doi: 10.1016/j.lungcan.2025.108847
35. Sharpe AH and Freeman GJ. The B7–CD28 superfamily. Nat Rev Immunol. (2002) 2:116–26. doi: 10.1038/nri727
36. Kim GR and Choi JM. Current understanding of cytotoxic T lymphocyte antigen-4 (CTLA-4) signaling in T-cell biology and disease therapy. Mol Cells. (2022) 45:513–21. doi: 10.14348/molcells.2022.2056
37. Tufail M, Jiang CH, and Li N. Immune evasion in cancer: mechanisms and cutting-edge therapeutic approaches. Signal Transduct Target Ther. (2025) 10:227. doi: 10.1038/s41392-025-02280-1
38. Li T, Gao S, Dong D, Chen Y, and Li S. Research progress and future perspectives of prodrug strategies for immune checkpoint inhibitors in cancer immunotherapy. Crit Rev Oncol Hematol. (2025) 214:104905. doi: 10.1016/j.critrevonc.2025.104905
39. Corsello A, Paragliola RM, Torino F, and Salvatori R. Hypophysitis associated with immune checkpoint inhibitors. Endocrin Metab Clin. (2025) 54:685–702. doi: 10.1016/j.ecl.2025.06.009
40. Cruz Carreras MT, González Landrón F, López N, Padrón Alcántara L, Markides DM, Burk KJ, et al. Hematologic immune-related adverse effects of immune checkpoint inhibitors: a review. Support Care Cancer. (2025) 33:912. doi: 10.1007/s00520-025-09952-2
41. Liu Y and Zheng P. Preserving the CTLA-4 checkpoint for safer and more effective cancer immunotherapy. Trends Pharmacol Sci. (2020) 41:4–12. doi: 10.1016/j.tips.2019.11.003
42. Morad G, Helmink BA, Sharma P, and Wargo JA. Hallmarks of response, resistance, and toxicity to immune checkpoint blockade. Cell. (2021) 184:5309–37. doi: 10.1016/j.cell.2021.09.020
43. Robert C. LAG-3 and PD-1 blockade raises the bar for melanoma. Nat Cancer. (2021) 2:1251–3. doi: 10.1038/s43018-021-00276-8
44. Huang RY, Francois A, McGray AR, Miliotto A, and Odunsi K. Compensatory upregulation of PD-1, LAG-3, and CTLA-4 limits the efficacy of single-agent checkpoint blockade in metastatic ovarian cancer. Oncoimmunology. (2017) 6:e1249561. doi: 10.1080/2162402X.2016.1249561
45. Koyama S, Akbay EA, Li YY, Herter-Sprie GS, Buczkowski KA, Richards WG, et al. Adaptive resistance to therapeutic PD-1 blockade is associated with upregulation of alternative immune checkpoints. Nat Commun. (2016) 7. doi: 10.1038/ncomms10501
46. Limagne E, Richard C, Thibaudin M, Fumet JD, Truntzer C, Lagrange A, et al. Tim-3/galectin-9 pathway and mMDSC control primary and secondary resistances to PD-1 blockade in lung cancer patients. Oncoimmunology. (2019) 8:e1564505. doi: 10.1080/2162402X.2018.1564505
47. Saleh R, Toor SM, Khalaf S, and Elkord E. Breast cancer cells and PD-1/PD-L1 blockade upregulate the expression of PD-1, CTLA-4, TIM-3 and LAG-3 immune checkpoints in CD4(+) T cells. Vaccines (Basel). (2019) 7. doi: 10.3390/vaccines7040149
48. Grosso JF, Kelleher CC, Harris TJ, Maris CH, Hipkiss EL, De Marzo A, et al. LAG-3 regulates CD8+ T cell accumulation and effector function in murine self- and tumor-tolerance systems. J Clin Invest. (2007) 117:3383–92. doi: 10.1172/JCI31184
49. Woo S, Turnis ME, Goldberg MV, Bankoti J, Selby M, Nirschl CJ, et al. Immune inhibitory molecules LAG-3 and PD-1 synergistically regulate T-cell function to promote tumoral immune escape. Cancer Res. (2012) 72:917–27. doi: 10.1158/0008-5472.CAN-11-1620
50. Wang J, Klein C, Cochran JR, Sockolosky J, and Lippow SM. Exploring new frontiers in LAG-3 biology and therapeutics. Trends Pharmacol Sci (Regular ed.). (2025) 46:638–52. doi: 10.1016/j.tips.2025.05.008
51. Sakuishi K, Apetoh L, Sullivan JM, Blazar BR, Kuchroo VK, and Anderson AC. Targeting Tim-3 and PD-1 pathways to reverse T cell exhaustion and restore anti-tumor immunity. J Exp Med. (2010) 207:2187–94. doi: 10.1084/jem.20100643
52. Fourcade J, Sun Z, Benallaoua M, Guillaume P, Luescher IF, Sander C, et al. Upregulation of Tim-3 and PD-1 expression is associated with tumor antigen–specific CD8+ T cell dysfunction in melanoma patients. J Exp Med. (2010) 207:2175–86. doi: 10.1084/jem.20100637
53. Harding JJ, Moreno V, Bang Y, Hong MH, Patnaik A, Trigo J, et al. Blocking TIM-3 in treatment-refractory advanced solid tumors: A phase ia/b study of LY3321367 with or without an anti-PD-L1 antibody. Clin Cancer Res. (2021) 27:2168–78. doi: 10.1158/1078-0432.CCR-20-4405
54. Curigliano G, Gelderblom H, Mach N, Doi T, Tai D, Forde PM, et al. Phase I/ib clinical trial of sabatolimab, an anti–TIM-3 antibody, alone and in combination with spartalizumab, an anti–PD-1 antibody, in advanced solid tumors. Clin Cancer Res. (2021) 27:3620–9. doi: 10.1158/1078-0432.CCR-20-4746
55. Swamydas M, Murphy EV, Ignatz-Hoover JJ, Malek E, and Driscoll JJ. Deciphering mechanisms of immune escape to inform immunotherapeutic strategies in multiple myeloma. J Hematol Oncol. (2022) 15. doi: 10.1186/s13045-022-01234-2
56. Tian Y, Zhai X, Han A, Zhu H, and Yu J. Potential immune escape mechanisms underlying the distinct clinical outcome of immune checkpoint blockades in small cell lung cancer. J Hematol Oncol. (2019) 12. doi: 10.1186/s13045-019-0753-2
57. Chauvin JM, Pagliano O, Fourcade J, Sun Z, Wang H, Sander C, et al. TIGIT and PD-1 impair tumor antigen-specific CD8+ T cells in melanoma patients. J Clin Invest. (2015) 125:2046–58. doi: 10.1172/JCI80445
58. Hu F, Wang W, Fang C, and Bai C. TIGIT presents earlier expression dynamic than PD-1 in activated CD8+ T cells and is upregulated in non-small cell lung cancer patients. Exp Cell Res. (2020) 396:112260. doi: 10.1016/j.yexcr.2020.112260
59. Kong Y, Zhu L, Schell TD, Zhang J, Claxton DF, Ehmann WC, et al. T-cell immunoglobulin and ITIM domain (TIGIT) associates with CD8+ T-cell exhaustion and poor clinical outcome in AML patients. Clin Cancer Res. (2016) 22:3057–66. doi: 10.1158/1078-0432.CCR-15-2626
60. Harjunpää H and Guillerey C. TIGIT as an emerging immune checkpoint. Clin Exp Immunol. (2020) 200:108–19. doi: 10.1111/cei.13407
61. Cui H, Hamad M, and Elkord E. TIGIT in cancer: from mechanism of action to promising immunotherapeutic strategies. Cell Death Dis. (2025) 16:664. doi: 10.1038/s41419-025-07984-4
62. Ma S, Dahabieh MS, Mann TH, Zhao S, McDonald B, Song WS, et al. Nutrient-driven histone code determines exhausted CD8(+) T cell fates. Science. (2025) 387:j3020. doi: 10.1126/science.adj3020
63. Li H, Mu W, Zhao A, Xiao S, Huo C, Zhao H, et al. Metabolic reprogramming and CD8(+) T-cell exhaustion during chronic HBV infection. Liver Int. (2025) 45:e70402. doi: 10.1111/liv.70402
64. Fu Z, Li M, Zhou H, Zhong X, Zhang Z, Meng X, et al. Endoplasmic reticulum stress orchestrates tumor metabolism and immunity: new insights into immunometabolic therapeutics. Front Immunol. (2025) 16:1674163. doi: 10.3389/fimmu.2025.1674163
65. Park B, Kim J, Baylink DJ, Hino C, Kwon C, Tran V, et al. Nutrient-gene therapy as a strategy to enhance CAR T cell function and overcome barriers in the tumor microenvironment. J Transl Med. (2025) 23:618–33. doi: 10.1186/s12967-025-06606-z
66. Sun RX, Liu YF, Sun YS, Zhou M, Wang Y, Shi BZ, et al. GPC3-targeted CAR-T cells expressing GLUT1 or AGK exhibit enhanced antitumor activity against hepatocellular carcinoma. Acta Pharmacol Sin. (2024) 45:1937–50. doi: 10.1038/s41401-024-01287-8
67. Guerrero JA, Klysz DD, Chen Y, Malipatlolla M, Lone J, Fowler C, et al. GLUT1 overexpression in CAR-T cells induces metabolic reprogramming and enhances potency. Nat Commun. (2024) 15:8658. doi: 10.1038/s41467-024-52666-y
68. Shi Y, Kotchetkov IS, Dobrin A, Hanina SA, Rajasekhar VK, Healey JH, et al. GLUT1 overexpression enhances CAR T cell metabolic fitness and anti-tumor efficacy. Mol Ther. (2024) 32:2393–405. doi: 10.1016/j.ymthe.2024.05.006
69. Ma G, Li C, Zhang Z, Liang Y, Liang Z, Chen Y, et al. Targeted glucose or glutamine metabolic therapy combined with PD-1/PD-L1 checkpoint blockade immunotherapy for the treatment of tumors - mechanisms and strategies. Front Oncol. (2021) 11:697894. doi: 10.3389/fonc.2021.697894
70. Kim J, Kim Y, La J, Park WH, Kim H, Park SH, et al. Supplementation with a high-glucose drink stimulates anti-tumor immune responses to glioblastoma via gut microbiota modulation. Cell Rep (Cambridge). (2023) 42:113220. doi: 10.1016/j.celrep.2023.113220
71. Rahman MA, Yadab MK, and Ali MM. Emerging role of extracellular pH in tumor microenvironment as a therapeutic target for cancer immunotherapy. Cells (Basel Switzerland). (2024) 13:1924. doi: 10.3390/cells13221924
72. Kumagai S, Koyama S, Itahashi K, Tanegashima T, Lin YT, Togashi Y, et al. Lactic acid promotes PD-1 expression in regulatory T cells in highly glycolytic tumor microenvironments. Cancer Cell. (2022) 40:201–18. doi: 10.1016/j.ccell.2022.01.001
73. Wang Z, Dai Z, Zhang H, Liang X, Zhang X, Wen Z, et al. Tumor-secreted lactate contributes to an immunosuppressive microenvironment and affects CD8 T-cell infiltration in glioblastoma. Front Immunol. (2023) 14:894853. doi: 10.3389/fimmu.2023.894853
74. Gu XY, Yang JL, Lai R, Zhou ZJ, Tang D, Hu L, et al. Impact of lactate on immune cell function in the tumor microenvironment: mechanisms and therapeutic perspectives. Front Immunol. (2025) 16:1563303. doi: 10.3389/fimmu.2025.1563303
75. Oh W, Kim A, Dhawan D, Knapp DW, and Lim SO. Lactic acid inhibits the interaction between PD-L1 protein and PD-L1 antibody in the PD-1/PD-L1 blockade therapy-resistant tumor. Mol Ther. (2025) 33:723–33. doi: 10.1016/j.ymthe.2024.12.044
76. Sheppard S, Santosa EK, Lau CM, Violante S, Giovanelli P, Kim H, et al. Lactate dehydrogenase A-dependent aerobic glycolysis promotes natural killer cell anti-viral and anti-tumor function. Cell Rep. (2021) 35:109210. doi: 10.1016/j.celrep.2021.109210
77. Zhou P, Chang W, Gong D, Xia J, Chen W, Huang L, et al. High dietary fructose promotes hepatocellular carcinoma progression by enhancing O-GlcNAcylation via microbiota-derived acetate. Cell Metab. (2023) 35:1961–75. doi: 10.1016/j.cmet.2023.09.009
78. Zhou P and Chi H. Fructose sweetens the adipocyte-T cell alliance against tumors. Cell Metab. (2023) 35:2093–4. doi: 10.1016/j.cmet.2023.11.004
79. Schild T, Wallisch P, Zhao Y, Wang Y, Haughton L, Chirayil R, et al. Metabolic engineering to facilitate anti-tumor immunity. Cancer Cell. (2025) 43:552–62. doi: 10.1016/j.ccell.2025.02.004
80. Zhang Y, Yu X, Bao R, Huang H, Gu C, Lv Q, et al. Dietary fructose-mediated adipocyte metabolism drives antitumor CD8+ T cell responses. Cell Metab. (2023) 35:2107–18. doi: 10.1016/j.cmet.2023.09.011
81. Zhao S, Jang C, Liu J, Uehara K, Gilbert M, Izzo L, et al. Dietary fructose feeds hepatic lipogenesis via microbiota-derived acetate. Nature. (2020) 579:586–91. doi: 10.1038/s41586-020-2101-7
82. He Y, Fu L, Li Y, Wang W, Gong M, Zhang J, et al. Gut microbial metabolites facilitate anticancer therapy efficacy by modulating cytotoxic CD8+ T cell immunity. Cell Metab. (2021) 33:988–1000. doi: 10.1016/j.cmet.2021.03.002
83. Chapman NM and Chi H. Metabolic adaptation of lymphocytes in immunity and disease. Immunity. (2022) 55:14–30. doi: 10.1016/j.immuni.2021.12.012
84. Qiu Y, Su Y, Xie E, Cheng H, Du J, Xu Y, et al. Mannose metabolism reshapes T cell differentiation to enhance anti-tumor immunity. Cancer Cell. (2025) 43:103–21. doi: 10.1016/j.ccell.2024.11.003
85. Du X, Li W, Li G, Guo C, Tang X, Bao R, et al. Diet-derived galactose reprograms hepatocytes to prevent T cell exhaustion and elicit antitumour immunity. Nat Cell Biol. (2025) 27:1357–66. doi: 10.1038/s41556-025-01716-8
86. Zheng Y, Yao Y, Ge T, Ge S, Jia R, Song X, et al. Amino acid metabolism reprogramming: shedding new light on T cell anti-tumor immunity. J Exp Clin Cancer Res. (2023) 42:291. doi: 10.1186/s13046-023-02845-4
87. Altman BJ, Stine ZE, and Dang CV. From Krebs to clinic: glutamine metabolism to cancer therapy. Nat Rev Cancer. (2016) 16:619–34. doi: 10.1038/nrc.2016.71
88. Xiang L, Mou J, Shao B, Wei Y, Liang H, Takano N, et al. Glutaminase 1 expression in colorectal cancer cells is induced by hypoxia and required for tumor growth, invasion, and metastatic colonization. Cell Death Dis. (2019) 10:40. doi: 10.1038/s41419-018-1291-5
89. Cruzat V, Macedo RM, Noel KK, Curi R, and Newsholme P. Glutamine: metabolism and immune function, supplementation and clinical translation. Nutrients. (2018) 10. doi: 10.3390/nu10111564
90. Wang W, Guo MN, Li N, Pang DQ, and Wu JH. Glutamine deprivation impairs function of infiltrating CD8(+) T cells in hepatocellular carcinoma by inducing mitochondrial damage and apoptosis. World J Gastrointest Oncol. (2022) 14:1124–40. doi: 10.4251/wjgo.v14.i6.1124
91. Huang R, Wang H, Hong J, Wu J, Huang O, He J, et al. Targeting glutamine metabolic reprogramming of SLC7A5 enhances the efficacy of anti-PD-1 in triple-negative breast cancer. Front Immunol. (2023) 14:1251643. doi: 10.3389/fimmu.2023.1251643
92. Leone RD, Zhao L, Englert JM, Sun IM, Oh MH, Sun IH, et al. Glutamine blockade induces divergent metabolic programs to overcome tumor immune evasion. Science. (2019) 366:1013–21. doi: 10.1126/science.aav2588
93. Tang Y, Wang S, Li Y, Yuan C, Zhang J, Xu Z, et al. Simultaneous glutamine metabolism and PD-L1 inhibition to enhance suppression of triple-negative breast cancer. J Nanobiotechnology. (2022) 20:216. doi: 10.1186/s12951-022-01424-7
94. Byun JK, Park M, Lee S, Yun JW, Lee J, Kim JS, et al. Inhibition of glutamine utilization synergizes with immune checkpoint inhibitor to promote antitumor immunity. Mol Cell. (2020) 80:592–606. doi: 10.1016/j.molcel.2020.10.015
95. Zhang X, Tu S, Wang Y, Xu B, and Wan F. Mechanism of taurine-induced apoptosis in human colon cancer cells. Acta Bioch Bioph Sin. (2014) 46:261–72. doi: 10.1093/abbs/gmu004
96. Tu S, Zhang X, Luo D, Liu Z, Yang X, Wan H, et al. Effect of taurine on the proliferation and apoptosis of human hepatocellular carcinoma HepG2 cells. Exp Ther Med. (2015) 10:193–200. doi: 10.3892/etm.2015.2476
97. Cao T, Zhang W, Wang Q, Wang C, Ma W, Zhang C, et al. Cancer SLC6A6-mediated taurine uptake transactivates immune checkpoint genes and induces exhaustion in CD8+ T cells. Cell. (2024). doi: 10.1016/j.cell.2024.03.011
98. Ping Y, Shan J, Liu Y, Liu F, Wang L, Liu Z, et al. Taurine enhances the antitumor efficacy of PD-1 antibody by boosting CD8+ T cell function. Cancer Immunology Immunother. (2023) 72:1015–27. doi: 10.1007/s00262-022-03308-z
99. Norian LA, Rodriguez PC, O’Mara LA, Zabaleta J, Ochoa AC, Cella M, et al. Tumor-infiltrating regulatory dendritic cells inhibit CD8+ T cell function via L-arginine metabolism. Cancer Res. (2009) 69:3086–94. doi: 10.1158/0008-5472.CAN-08-2826
100. Rodriguez PC, Ochoa AC, and Al-Khami AA. Arginine metabolism in myeloid cells shapes innate and adaptive immunity. Front Immunol. (2017) 8:93. doi: 10.3389/fimmu.2017.00093
101. Pilanc P, Wojnicki K, Roura AJ, Cyranowski S, Ellert-Miklaszewska A, Ochocka N, et al. A novel oral arginase 1/2 inhibitor enhances the antitumor effect of PD-1 inhibition in murine experimental gliomas by altering the immunosuppressive environment. Front Oncol. (2021) 11:703465. doi: 10.3389/fonc.2021.703465
102. Niu F, Yu Y, Li Z, Ren Y, Li Z, Ye Q, et al. Arginase: An emerging and promising therapeutic target for cancer treatment. BioMed Pharmacother. (2022) 149:112840. doi: 10.1016/j.biopha.2022.112840
103. Aaboe JM, Ugel S, Linder HM, Carretta M, Perez-Penco M, Weis-Banke SE, et al. Arginase 1-based immune modulatory vaccines induce anticancer immunity and synergize with anti-PD-1 checkpoint blockade. Cancer Immunol Res. (2021) 9:1316–26. doi: 10.1158/2326-6066.CIR-21-0280
104. Qin R, Zhao C, Wang CJ, Xu W, Zhao JY, Lin Y, et al. Tryptophan potentiates CD8(+) T cells against cancer cells by TRIP12 tryptophanylation and surface PD-1 downregulation. J Immunother Cancer. (2021) 9. doi: 10.1136/jitc-2021-002840
105. Malczewski AB, Coward JI, Ketheesan N, and Navarro S. Immunometabolism: The role of gut-derived microbial metabolites in optimising immune response during checkpoint inhibitor therapy. Clin Trans Med. (2025) 15:e70472. doi: 10.1002/ctm2.70472
106. Lorentzen CL, Kjeldsen JW, Ehrnrooth E, Andersen MH, and Marie SI. Long-term follow-up of anti-PD-1 naïve patients with metastatic melanoma treated with IDO/PD-L1 targeting peptide vaccine and nivolumab. J Immunother Cancer. (2023) 11. doi: 10.1136/jitc-2023-006755
107. Liang X, Gao H, Xiao J, Han S, He J, Yuan R, et al. Abrine, an IDO1 inhibitor, suppresses the immune escape and enhances the immunotherapy of anti-PD-1 antibody in hepatocellular carcinoma. Front Immunol. (2023) 14:1185985. doi: 10.3389/fimmu.2023.1185985
108. Holmgaard RB, Zamarin D, Munn DH, Wolchok JD, and Allison JP. Indoleamine 2,3-dioxygenase is a critical resistance mechanism in antitumor T cell immunotherapy targeting CTLA-4. J Exp Med. (2013) 210:1389–402. doi: 10.1084/jem.20130066
109. Manzo T, Prentice BM, Anderson KG, Raman A, Schalck A, Codreanu GS, et al. Accumulation of long-chain fatty acids in the tumor microenvironment drives dysfunction in intrapancreatic CD8+ T cells. J Exp Med. (2020) 217. doi: 10.1084/jem.20191920
110. Song J, Wang Y, Fan X, Wu H, Han J, Yang M, et al. Trans-vaccenic acid inhibits proliferation and induces apoptosis of human nasopharyngeal carcinoma cells via a mitochondrial-mediated apoptosis pathway. Lipids Health Dis. (2019) 18. doi: 10.1186/s12944-019-0993-8
111. Li M, van Esch BCAM, Wagenaar GTM, Garssen J, Folkerts G, and Henricks PAJ. Pro- and anti-inflammatory effects of short chain fatty acids on immune and endothelial cells. Eur J Pharmacol. (2018) 831:52–9. doi: 10.1016/j.ejphar.2018.05.003
112. Bachem A, Makhlouf C, Binger KJ, de Souza DP, Tull D, Hochheiser K, et al. Microbiota-derived short-chain fatty acids promote the memory potential of antigen-activated CD8+ T cells. Immunity. (2019) 51:285–97. doi: 10.1016/j.immuni.2019.06.002
113. Fan H, Xia S, Xiang J, Li Y, Ross MO, Lim SA, et al. Trans-vaccenic acid reprograms CD8+ T cells and anti-tumour immunity. Nature. (2023) 623:1034–43. doi: 10.1038/s41586-023-06749-3
114. Nava Lauson CB, Tiberti S, Corsetto PA, Conte F, Tyagi P, Machwirth M, et al. Linoleic acid potentiates CD8+ T cell metabolic fitness and antitumor immunity. Cell Metab. (2023) 35:633–50. doi: 10.1016/j.cmet.2023.02.013
115. van Gorkom G, Klein Wolterink R, Van Elssen C, Wieten L, Germeraad W, and Bos G. Influence of vitamin C on lymphocytes: an overview. Antioxidants. (2018) 7:41. doi: 10.3390/antiox7030041
116. Yun J, Mullarky E, Lu C, Bosch KN, Kavalier A, Rivera K, et al. Vitamin C selectively kills KRAS and BRAF mutant colorectal cancer cells by targeting GAPDH. Science. (2015) 350:1391–6. doi: 10.1126/science.aaa5004
117. Asahi T, Abe S, Tajika Y, Rodewald HR, Sexl V, Takeshima H, et al. Retinoic acid receptor activity is required for the maintenance of type 1 innate lymphoid cells. Int Immunol. (2023) 35:147–55. doi: 10.1093/intimm/dxac057
118. Liu G, Quan Q, Pan L, Duan H, Zhang G, Li K, et al. Retinoic acid enhances gammadelta T cell cytotoxicity in nasopharyngeal carcinoma by reversing immune exhaustion. Cell Commun Signal. (2025) 23:156. doi: 10.1186/s12964-025-02161-8
119. Hao Y, Li R, and Min Y. Platinum-based twin drug modulates tumor-infiltrating immune cells to improve immune checkpoint blockade therapy. J Med Chem. (2023) 66:13607–21. doi: 10.1021/acs.jmedchem.3c00946
120. Wei C, Huang L, Kreh B, Liu X, Tyutyunyk-Massey L, Kawakami M, et al. A novel retinoic acid receptor-γ agonist antagonizes immune checkpoint resistance in lung cancers by altering the tumor immune microenvironment. Sci REP-UK. (2023) 13:14907. doi: 10.1038/s41598-023-41690-5
121. Huijskens MJAJ, Walczak M, Sarkar S, Atrafi F, Senden-Gijsbers BLMG, Tilanus MGJ, et al. Ascorbic acid promotes proliferation of natural killer cell populations in culture systems applicable for natural killer cell therapy. Cytotherapy. (2015) 17:613–20. doi: 10.1016/j.jcyt.2015.01.004
122. Zhao X, Liu M, Li C, Liu X, Zhao J, Ma H, et al. High dose Vitamin C inhibits PD-L1 by ROS-pSTAT3 signal pathway and enhances T cell function in TNBC. Int ImmunopharmacoL. (2024) 126:111321. doi: 10.1016/j.intimp.2023.111321
123. Luchtel RA, Bhagat T, Pradhan K, Jacobs WR, Levine M, Verma A, et al. High-dose ascorbic acid synergizes with anti-PD1 in a lymphoma mouse model. Proc Natl Acad Sci. (2020) 117:1666–77. doi: 10.1073/pnas.1908158117
124. Magrì A, Germano G, Lorenzato A, Lamba S, Chilà R, Montone M, et al. High-dose vitamin C enhances cancer immunotherapy. Sci Transl Med. (2020) 12. doi: 10.1126/scitranslmed.aay8707
125. Garland CF, Comstock GW, Garland FC, Helsing KJ, Shaw EK, and Gorham ED. Serum 25-hydroxyvitamin D and colon cancer: eight-year prospective study. Lancet. (1989) 2:1176–8. doi: 10.1016/s0140-6736(89)91789-3
126. Budhathoki S, Hidaka A, Yamaji T, Sawada N, Tanaka-Mizuno S, Kuchiba A, et al. Plasma 25-hydroxyvitamin D concentration and subsequent risk of total and site specific cancers in Japanese population: large case-cohort study within Japan Public Health Center-based Prospective Study cohort. BMJ. (2018) 360:k671. doi: 10.1136/bmj.k671
127. Shirazi L, Almquist M, Borgquist S, Malm J, and Manjer J. Serum vitamin D (25OHD3) levels and the risk of different subtypes of breast cancer: A nested case–control study. Breast. (2016) 28:184–90. doi: 10.1016/j.breast.2016.06.002
128. Colotta F, Jansson B, and Bonelli F. Modulation of inflammatory and immune responses by vitamin D. J Autoimmun. (2017) 85:78–97. doi: 10.1016/j.jaut.2017.07.007
129. Li P, Zhu X, Cao G, Wu R, Li K, Yuan W, et al. 1α,25(OH)2 D3 reverses exhaustion and enhances antitumor immunity of human cytotoxic T cells. J Immunother Cancer. (2022) 10:e3477. doi: 10.1136/jitc-2021-003477
130. Li K, Lu E, Wang Q, Xu R, Yuan W, Wu R, et al. Serum vitamin D deficiency is associated with increased risk of γδ T cell exhaustion in HBV-infected patients. Immunology. (2024) 171:31–44. doi: 10.1111/imm.13696
131. Galus L, Michalak M, Lorenz M, Stoinska-Swiniarek R, Tusien MD, Galus A, et al. Vitamin D supplementation increases objective response rate and prolongs progression-free time in patients with advanced melanoma undergoing anti-PD-1 therapy. Cancer-Am Cancer Soc. (2023) 129:2047–55. doi: 10.1002/cncr.34718
132. Giampazolias E, Pereira DCM, Lam KC, Lim K, Cardoso A, Piot C, et al. Vitamin D regulates microbiome-dependent cancer immunity. Science. (2024) 384:428–37. doi: 10.1126/science.adh7954
133. Wang Y, Wang F, Wang L, Qiu S, Yao Y, Yan C, et al. NAD+ supplement potentiates tumor-killing function by rescuing defective TUB-mediated NAMPT transcription in tumor-infiltrated T cells. Cell Rep. (2021) 36:109516. doi: 10.1016/j.celrep.2021.109516
134. Bruzzone S, Fruscione F, Morando S, Ferrando T, Poggi A, Garuti A, et al. Catastrophic NAD+ depletion in activated T lymphocytes through Nampt inhibition reduces demyelination and disability in EAE. PLoS One. (2009) 4:e7897. doi: 10.1371/journal.pone.0007897
135. Zhao G, Yang X, Zhang C, Dong W, Dong F, Zhang J, et al. Supplementation with nicotinamide riboside attenuates t cell exhaustion and improves survival in sepsis. Shock. (2023) 60:238–47. doi: 10.1097/SHK.0000000000002153
136. Li Q, Zhang L, You W, Xu J, Dai J, Hua D, et al. PRDM1/BLIMP1 induces cancer immune evasion by modulating the USP22-SPI1-PD-L1 axis in hepatocellular carcinoma cells. Nat Commun. (2022) 13:7677. doi: 10.1038/s41467-022-35469-x
137. Hodi FS, O’Day SJ, McDermott DF, Weber RW, Sosman JA, Haanen JB, et al. Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med. (2010) 363:711–23. doi: 10.1056/NEJMoa1003466
138. Cai L, Li Y, Tan J, Xu L, and Li Y. Targeting LAG-3, TIM-3, and TIGIT for cancer immunotherapy. J Hematol Oncol. (2023) 16. doi: 10.1186/s13045-023-01499-1
139. Zhou Z, Dong D, Yuan Y, Luo J, Liu XD, Chen LY, et al. Single cell atlas reveals multilayered metabolic heterogeneity across tumour types. Ebiomedicine. (2024) 109:105389. doi: 10.1016/j.ebiom.2024.105389
140. Kim J and DeBerardinis RJ. Mechanisms and implications of metabolic heterogeneity in cancer. Cell Metab. (2019) 30:434–46. doi: 10.1016/j.cmet.2019.08.013
141. Kuo CY and Ann DK. When fats commit crimes: fatty acid metabolism, cancer stemness and therapeutic resistance. Cancer Commun (Lond). (2018) 38:47. doi: 10.1186/s40880-018-0317-9
142. Lee H, Park S, Lee J, Lee C, Kang H, Kang J, et al. Lipid metabolism in cancer stem cells: reprogramming, mechanisms, crosstalk, and therapeutic approaches. Cell Oncol (Dordr). (2025) 48:1181–201. doi: 10.1007/s13402-025-01081-6
143. Goodwin J, Neugent ML, Lee SY, Choe JH, Choi H, Jenkins D, et al. The distinct metabolic phenotype of lung squamous cell carcinoma defines selective vulnerability to glycolytic inhibition. Nat Commun. (2017) 8:15503. doi: 10.1038/ncomms15503
144. Chicklore S, Goh V, Siddique M, Roy A, Marsden PK, and Cook GJR. Quantifying tumour heterogeneity in 18F-FDG PET/CT imaging by texture analysis. Eur J Nucl Med Mol I. (2013) 40:133–40. doi: 10.1007/s00259-012-2247-0
145. Hensley CT, Faubert B, Yuan Q, Lev-Cohain N, Jin E, Kim J, et al. Metabolic heterogeneity in human lung tumors. Cell. (2016) 164:681–94. doi: 10.1016/j.cell.2015.12.034
146. Faubert B, Li KY, Cai L, Hensley CT, Kim J, Zacharias LG, et al. Lactate metabolism in human lung tumors. Cell. (2017) 171:358–71. doi: 10.1016/j.cell.2017.09.019
147. Courtney KD, Bezwada D, Mashimo T, Pichumani K, Vemireddy V, Funk AM, et al. Isotope tracing of human clear cell renal cell carcinomas demonstrates suppressed glucose oxidation in vivo. Cell Metab. (2018) 28:793–800. doi: 10.1016/j.cmet.2018.07.020
148. Grashei M, Biechl P, Schilling F, and Otto AM. Conversion of hyperpolarized [1-13C]Pyruvate in breast cancer cells depends on their Malignancy, metabolic program and nutrient microenvironment. Cancers. (2022) 14:1845. doi: 10.3390/cancers14071845
Keywords: antitumor immunity, exhausted T cells, immune checkpoint inhibitors, immunotherapy, nutrients
Citation: Xu Y, Yuan W, Li K and Li P (2025) Nutritional intervention alleviates T cell exhaustion and empowers anti-tumor immunity. Front. Immunol. 16:1689317. doi: 10.3389/fimmu.2025.1689317
Received: 22 August 2025; Accepted: 08 December 2025; Revised: 08 December 2025;
Published: 19 December 2025.
Edited by:
Cosima T. Baldari, University of Siena, ItalyReviewed by:
Jose Aramburu, Universidad Pompeu Fabra, SpainCopyright © 2025 Xu, Yuan, Li and Li. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
*Correspondence: Ke Li, bGlrZTM5QG1haWwuc3lzdS5lZHUuY24=; Peng Li, cGVuZ2xpMTk5MUBqbnUuZWR1LmNu
†These authors have contributed equally to this work and share first authorship