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Open Access

Targeting tumor-infiltrating regulatory T cells based on immunometabolism

Na Li and Dexue Tian
Cancer Biology & Medicine February 2026, 23 (2) 186-200; DOI: https://doi.org/10.20892/j.issn.2095-3941.2025.0645

Abstract

The immune checkpoint blockade (ICB) approach in cancer therapy involves the disruption of immune checkpoint inhibitory signals on tumor-specific CD8+ T cells, thereby reinstating the immune activity of CD8+ T cells and yielding therapeutic efficacy. However, due to the co-expression of immune checkpoint molecules, such as CTLA-4 and PD-1 on tumor-infiltrating Tregs (TI-Tregs) and conventional T cells (Tconvs), immune checkpoint inhibitors (ICIs) inadvertently amplify the immunosuppressive activity of Tregs while targeting CD8+ T cells, which contributes to the failure of immune therapy. Conventional strategies targeting Tregs, including ICI/conventional kinase and chemokine/chemokine receptor blockade, generally induce systemic Treg depletion, which triggers autoimmune diseases. Thus, achieving high selectivity and specificity in targeting TI-Tregs is of paramount importance in mitigating adverse immunologic reactions. Targeting metabolism-based TI-Tregs has been shown to enhance target precision, providing potential for the development of adjunctive immunotherapeutic strategies. This article explores the reciprocal interaction between TI-Tregs and the tumor microenvironment (TME), elucidating metabolic reprogramming, while envisioning plausible high-selectivity targets for TI-Tregs without compromising systemic immune homeostasis and immune reactivity of effector T cells.

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Introduction

Regulatory T cells (Tregs) are critical mediators in maintaining immune tolerance, achieving immune balance by suppressing inflammatory responses and excessive immune activation1. However, tumor-infiltrating regulatory T cells (TI-Tregs) function as accomplices to tumors within the tumor microenvironment (TME). Together, TI-Tregs and tumors suppress the cytotoxic activity of effector T cells against tumor cells, leading to functional exhaustion of effector T cells and facilitating tumor immune escape2,3. Furthermore, immune checkpoint blockade (ICB) therapy, which is achieved with anti-PD-1 antibodies, induces an increase in the number and immunosuppressive activity of Tregs in tumor tissues and the peripheral circulation4. This effect contributes to immune-related adverse events (irAEs) and tumor hyperprogression5, complications that persist even in the context of neoadjuvant ICB therapy6. Studies have demonstrated that high Treg infiltration is associated with poorer immune prognosis in various malignancies7. Consequently, the abundance of Tregs within the TME and the frequency in the peripheral circulation can serve as immunologic predictors of tumor recurrence and metastasis8. Animal studies have shown that ICB therapy combined with Treg-targeting strategies can elicit potent anti-tumor immune responses9, even activating systemic and sustained CD8+ T cell-mediated anti-tumor immunity to suppress tumor recurrence and metastasis6. However, a critical drawback of targeting Tregs is the non-specific nature of current approaches. These therapies deplete Tregs not only in the tumor locale but also systemically, potentially causing severe autoimmune disorders and a profound disruption of immune homeostasis10,11. Therefore, identifying precise targets specific to TI-Tregs represents an effective pathway to prevent systemic Treg depletion. This strategy necessitates an in-depth investigation into the mechanisms allowing TI-Tregs to thrive and maintain potent immunosuppressive activity within the TME. Research must focus on how TI-Tregs remodel metabolic pathways in the metabolically challenging milieu characterized by hypoxia, and low glucose and high lactate levels. Building on these metabolic adaptations to discover highly specific TI-Treg targets is essential for overcoming the limitations of antibody-based cancer immunotherapies.

Origin and classification of TI-Tregs

The abundant immunosuppressive Tregs within tumor tissues may originate from the following sources, which are generated in response to tumor antigens: peripheral Tregs (pTregs); thymus-derived Tregs (tTregs); and antigen-induced Tregs (iTregs)12. tTregs develop from CD4+ T cell precursors in the thymus following stimulation by self-antigens presented by thymic epithelial cells. After maturation, tTregs migrate to peripheral tissues to maintain immune tolerance against self-antigens13,14. In contrast, pTregs differentiate from mature CD4+ T cells in the periphery and have a decisive role in balancing immune responses to foreign antigens, while preventing autoimmunity13. iTregs often arise from naïve T cells within the TME that differentiate under the influence of local antigens and cytokines15. Tregs can be further categorized into central Tregs (cTregs) and effector Tregs (eTregs) based on immunosuppressive potency in human peripheral lymphoid and tumor tissues16.

Three distinct subsets of Tregs have been identified, reflecting the phenotypic and functional heterogeneity16: ① FoxP3loCD25loCD45RA+ Tregs, Fraction I (Fr. I) are quiescent, non-activated Tregs with minimal immunosuppressive activity. ② FoxP3hiCD25hiCD45RA− Tregs (Fr. II) differentiate into eTregs upon T cell receptor (TCR) stimulation by antigens in the periphery or TME. Activated eTregs exhibit enhanced proliferation and potent suppressive capacity and actively express surface molecules, including the activation marker, CD44, effector molecules, such as programmed cell death protein-1 (PD-1), cytotoxic T-lymphocyte antigen 4 (CTLA-4), and T cell immunoreceptor with Ig and ITIM domains (TIGIT)17. Concurrently, activated eTregs increase the secretion of immunosuppressive cytokines, like interleukin-10 (IL-10), interleukin-35 (IL-35), and transforming growth factor-beta (TGF-β)12. ③ FoxP3loCD25loCD45RA− Tregs lack significant immunosuppressive function and can secrete pro-inflammatory cytokines16.

In summary, eTregs constitute < 5% of T cells in human peripheral blood but are highly enriched within the TME, where eTregs predominantly exert immunosuppressive effects18.

Immunosuppressive mechanisms mediated by TI-Tregs

Tumor tissues facilitate the recruitment and enrichment of Tregs within the TME by releasing chemokines (e.g., CCL5 and CCL22) and cytokines (e.g., TGF-β and IL-10)19, which interact with corresponding chemokine receptors (CKRs) on Tregs (e.g., CCR4, CCR8, CXCR4, and CXCR5)20. Tumor cells, through metabolic reprogramming, shape the TME into an immunosuppressive milieu characterized by hypoxia, and low glucose and high lactate levels21. This metabolic environment severely suppresses the cytotoxic activity of immune cells, particularly CD8+ T cells22. In contrast, Tregs maintain robust immunosuppressive functions, even under these metabolically restrictive conditions23. What accounts for this stark functional difference between CD8+ T cells and Tregs? Research indicates that the energy metabolism mechanisms within the TME are fundamentally distinct24. TI-Tregs exhibit metabolic flexibility, allowing TI-Tregs to adapt metabolic pathways, utilize tumor-derived metabolites, and thereby sustain immunosuppressive activity25. Furthermore, Tregs can actively suppress CD8+ T cell activation and metabolism through metabolic interference (Figure 1)26. For example, Tregs hydrolyze extracellular ATP to adenosine, which then binds to the A2A receptor on CD8+ T cells, inhibiting CD8+ T cell activation27. In addition, CTLA-4 expressed on Tregs can induce indoleamine 2,3-dioxygenase (IDO) production in antigen-presenting cells (APCs). IDO catabolizes tryptophan into kynurenine, leading to tryptophan starvation and subsequent apoptosis of effector T cells (Teffs)28.

Figure 1
Figure 1

Representation of Treg-mediated suppressive mechanisms. (A) Tregs suppress Teff activation via CTLA-4. Tregs use CTLA-4 to competitively bind CD80/86 on APCs, resulting in depletion of the co-stimulatory molecules via trans-endocytosis into Tregs. (B) Tregs secrete immunosuppressive cytokines and cytotoxic molecules. Tregs suppress Teffs and APCs through secretion of immunosuppressive cytokines (IL-10, IL-35, and TGF-β) and induce apoptosis via cytotoxic molecules (granzyme B and perforin). (C) Tregs starve Teffs by competitively depleting IL-2 via CD25. Treg-mediated sequestration of IL-2 via the high-affinity CD25 receptor deprives Teffs of essential trophic signals, inducing apoptosis, while concurrently attenuating the cytokine-dependent activation of APCs. (D) Tregs interfere with Teff metabolism. Tregs convert extracellular ATP into adenosine via CD39 and CD73; the resulting adenosine interacts with A2A/A2B receptors on Teffs and APCs to inhibit activation. In addition, Tregs induce APCs to produce IDO via an interaction with CTLA-4. IDO converts tryptophan into kynurenine, resulting in the “starvation death” of Teffs. A2BR, adenosine A2B receptor; AMP, adenosine monophosphate; APC, antigen-presenting cell; ATP, adenosine triphosphate; CD25, cluster of differentiation 25; CD28, cluster of differentiation 28; CD39, cluster of differentiation 39; CD73, cluster of differentiation 73; CD80/86, cluster of differentiation 80/86; CTLA-4, cytotoxic T-lymphocyte-associated protein 4; IDO, indoleamine 2,3-dioxygenase; IL-2, interleukin-2; LAG-3, lymphocyte activation gene-3; MHC II, major histocompatibility complex class II; PD-1, programmed death-1; TCR, T cell receptor; Teff, effector T cell; TGF-β, transforming growth factor-beta; TIGIT, T cell immunoreceptor with Ig and ITIM domains; TIM-3, T cell immunoglobulin and mucin-domain containing-3. Created using BioRender.com.

In addition to metabolic suppression, Tregs employ multiple other mechanisms to impede Teff function, as follows (Figure 1): ① Tregs disrupt the APC-Teff signaling axis through distinct molecular checkpoints (e.g., PD-1, CTLA-4, LAG-3, and TIGIT)29. CTLA-4 mediates the trans-endocytosis of CD80/86, depriving Teffs of CD28 co-stimulation to induce anergy30. TIGIT competitively sequesters CD155, abrogating CD226 activation while eliciting APC-derived IL-10 via reverse signaling31. LAG-3 outcompetes CD4 for MHC-II binding to impose steric hindrance on TCR engagement. PD-1 ligates PD-L1 to reinforce Treg stability, while attenuating pro-inflammatory cytokine release from APCs32. ② Tregs secrete immunosuppressive cytokines (e.g., IL-10, IL-35, and TGF-β), inhibiting the proliferation and activation of Teffs and APCs. ③ Tregs directly eliminate Teffs via the perforin/granzyme B-dependent cytolytic pathway, a process strictly licensed by TCR signaling and high IL-2 availability. Mechanistically, this process involves the polarized exocytosis of cytotoxic granules into the immunologic synapse, where granzyme B triggers a caspase-dependent apoptotic cascade within the Teff33. ④ Tregs express the high-affinity CD25 receptor, IL-2Rα, competitively consuming IL-2, and thereby limiting IL-2 availability for Teffs34.

In summary, Tregs exert potent immunosuppression by adaptively reprogramming metabolism within the TME and simultaneously disrupting the immunometabolism of CD8+ T cells. Consequently, therapeutic strategies targeting these specific Treg immunosuppressive mechanisms are now being extensively explored.

Conventional strategies for targeting TI-Tregs

Limitations of targeting TI-Tregs in ICB therapy

Tregs express CTLA-4, which exhibits high affinity for CD80/86 on APCs. This CTLA-r expression enables Tregs to competitively inhibit binding between CD28 on conventional T cells (Tconvs) and CD80/86, thereby impeding Tconv activation35 and forcing Tconvs into an anergic state. PD-1 is highly expressed on Teffs and Tregs within the TME. PD-1 ligation serves to restrain the over-expansion of Tregs, while PD-1 ligation by PD-L1 drives Teff exhaustion and apoptosis by attenuating TCR signaling36. The high frequency of PD-1+ Tregs remains a hallmark of a potent immunosuppressive niche, although PD-1 signaling acts as a “brake” on Treg proliferation; blockade of this pathway can inadvertently lead to Treg hyper-activation37.

Although current blockade therapies targeting CTLA-4 and PD-1 have demonstrated considerable efficacy in various malignancies38, PD-1 blockade paradoxically activates PD-1+ Tregs, thereby enhancing the immunosuppressive activity of TI-Tregs within tumors and contributing to treatment failure36. Furthermore, due to the lack of tumor tissue specificity in these targeting approaches, systemic Treg dysfunction is frequently induced. Studies utilizing CTLA-4 or PD-1 deficient mouse models have shown that most of the mice develop fatal autoimmune diseases due to Treg depletion12. Moreover, anti-CTLA-4 monotherapy has failed in several phase III or IV clinical trials and is associated with a higher incidence of irAEs compared to anti-PD-1/PD-L1 therapy39. The incidence of grade 3 and 4 irAEs can reach 90% in neoadjuvant settings by combining the anti-CTLA-4 antibody, ipilimumab, with the anti-PD-1 antibody, nivolumab, for melanoma patients40.

While extensive preclinical evidence suggests that integrating ICB therapy with Treg-targeting strategies enhances efficacy in various tumor models12, clinical translation remains challenging. Indeed, a substantial proportion of patients exhibit primary resistance to ICB and have a significant incidence of irAEs41. Specifically, dual CTLA-4/PD-1 blockade (e.g., ipilimumab + nivolumab) is associated with a markedly high grade 3–4 irAE incidence of approximately 59%42. Moreover, targeted systemic depletion of Tregs, such as via CCR4 (mogamulizumab) or CD25 (RG6292), often elicits severe autoimmune-like toxicities, including cutaneous reactions and gastrointestinal inflammation. These clinical observations underscore the profound risk of compromising peripheral immune tolerance when aggressively targeting the Treg compartment43,44. Consequently, the following critical challenge remains: how can the benefits of ICB therapy be extended to low- or non-responding patients without compromising safety through severe immune toxicities.

Exploratory research addressing TI-Treg targeting deficiencies

Genetic engineering of co-inhibitory receptors on TI-Tregs

To address the abovementioned therapeutic limitations, researchers developed HCAb4003-1, a fully human heavy-chain antibody (HCAb) comprising a CTLA-4-specific variable domain fused to an hIgG1 Fc region. This antibody exhibits high affinity for human CTLA-4 and effectively blocks the interaction with B7-1 (CD80) and B7-2 (CD86). Furthermore, owing to the compact molecular configuration and reduced molecular weight, HCAb4003-1 demonstrates superior tumor tissue penetration. In addition, due to the optimized Fc region, HCAb4003-1 exerts enhanced antibody-dependent cellular cytotoxicity (ADCC) in mouse models45. Further investigation is required to establish the safety and efficacy profile of HCAb4003-1, which is currently in preclinical development.

The CTLA-4-targeting monoclonal antibodies currently in clinical use, ipilimumab and tremelimumab, achieve relatively sustained efficacy primarily by enhancing Teff activity. However, induction of CTLA-4 lysosomal degradation in Tregs leads to systemic Treg depletion and frequent irAEs, which directly limit clinical utility46. To circumvent this issue, engineered antibodies, such as HL12 or HL32, have been designed. These antibodies dissociate from CTLA-4 after endocytosis, evade lysosomal degradation via an LRBA-dependent mechanism, and recycle back to the cell surface. This process helps maintain TI-Treg immunosuppressive function and reduces the incidence of autoimmune complications47.

Genetic engineering efforts are also targeting other immunosuppressive molecules on Tregs, such as LAG-3, TIGIT, and TIM-3. Several resulting monoclonal antibodies are under ongoing investigation, with the long-term efficacy still being evaluated48. For example, IMP321, a chimeric recombinant fusion protein antibody targeting LAG-3, effectively stimulates dendritic cell proliferation, enhances antigen presentation by APCs, and mitigates Treg-mediated immunosuppression49. IMP321 has shown antitumor activity in patients with metastatic melanoma, metastatic breast cancer, and advanced renal cell carcinoma50. Other anti-LAG-3 antibodies, including BMS-986016, LAG525, and INCAGN02385, are currently undergoing clinical trials as monotherapies or in combination with anti-PD-1 antibodies. In vitro and ex vivo studies indicate that TIGIT targeting significantly reduces Treg frequency and TGF-β1 secretion, while also suppressing the immunosuppressive function of myeloid-derived suppressor cells. Several anti-TIGIT antibodies, such as BGB-A1217, COM902, and IBI939, remain under investigation51. Furthermore, the combination of anti-TIM-3 and anti-PD-L1 antibodies delayed tumor growth in a mouse model of head and neck squamous cell carcinoma. This combination enhanced effector T cell cytotoxicity, reduced Treg abundance, and improved survival, although the therapeutic effect was not sustained. Analysis of recurrent tumors revealed that the number of Tregs rebounded to pre-treatment levels52.

Therefore, antibodies targeting co-inhibitory receptors on TI-Tregs remain an active area of exploration and development, yet the antibodies continue to be associated with varying degrees of irAEs53.

Targeting tumor necrosis factor receptors (TNFRs) and CKRs to deplete TI-Tregs

In addition to targeting the immunosuppressive molecules on Tregs, alternative strategies focus on interfering with other key modulators of TI-Treg function within the TME. These modulators include specific TNFRs such as GITR, OX40, and CD27, as well as CKRs, like CCR4, CCR8, CCR5, CCR10, and CKR ligands (e.g., CCL20)12.

TNFR2, encoded by the TNFRSF1B gene, is highly expressed on tumor cells and TI-Tregs54. Among Treg subsets, TNFR2+ Tregs exhibit the most potent immunosuppressive activity55. Mechanistically, TNFR2 signaling enhances the NF-κB pathway to upregulate PD-L1 expression on tumor cells, which promotes immune escape56. TNFR2 signaling also induces mitochondrial hyperpolarization and ROS-mediated DNA damage in CD8+ T cells, leading to programmed death57. Consequently, targeting TNFR2 can selectively deplete TNFR2+ TI-Tregs and alleviate suppression of CD8+ T cells. Several TNFR2-targeting agents are currently under clinical evaluation. Monoclonal antibodies, such as BI-1808 and LBL-019, block TNFR2–TNF-α interaction, deplete TI-Tregs via FcγR-dependent mechanisms, and promote T cell activation and IFN-γ release58,59. Other agents, including SIM-235, inhibit Treg proliferation by suppressing NF-κB signaling60. In addition, bispecific approaches (e.g., BsADC and FT10-Fab) targeting TNFR2 and CCR8 have shown enhanced efficacy and sustained immune activation in preclinical models61, particularly when combined with anti-PD-1 therapy62. Given the specific expression on TI-Tregs, TNFR2 represents a promising target for future cancer immunotherapy.

Research involving other TNF receptor superfamily members is also advancing. A study investigating the anti-GITR agonist, DTA-1, in hepatocellular carcinoma demonstrated the efficacy in reducing TI-Treg infiltration. However, DTA-1 failed to reactivate exhausted CD8+ T cells and induced a shift in macrophage polarization from the M1-to-M2 phenotype63. This undesirable M2 polarization was effectively reversed when DTA-1 was combined with a Toll-like receptor 4 (TLR4) agonist64. Further research using ex vivo cultures of hepatocellular carcinoma tissue revealed that combining anti-GITR with anti-PD-1 therapy enhances the proliferative response of CD4+ and CD8+ tumor-infiltrating lymphocytes (TILs) to tumor antigens presented by mRNA-transfected autologous B-lymphoblastoid cells. These TILs exhibit significantly enhanced proliferation with increased secretion of IFN-γ and granzyme B upon stimulation with CD3/CD28 antibodies65. Researchers developed a bispecific IgG1 antibody, the human CTLA-4 × OX40 antibody (ATOR-1015), that was created by fusing the Ig-like V-type domain of human CD86 (a natural CTLA-4 ligand) to an agonistic OX40 antibody. ATOR-1015 was shown to induce T cell activation and Treg depletion in vitro. ATOR-1015 exhibited good tumor infiltration, reduced local TI-Treg abundance, and increased the number and activity of CD8+ T cells in human OX40 transgenic mouse models. Furthermore, ATOR-1015 demonstrated significant TI-Treg-specific depletion and sustained CD8+ T cell immunity across various syngeneic mouse models, including bladder, colon, and pancreatic cancers66.

Mogamulizumab, a recombinant humanized monoclonal antibody developed for cutaneous T-cell lymphoma, has shown promising clinical efficacy. Mogamulizumab significantly reduced the levels of CCR4+ T cells and CCR4+ Tregs within the TME67. Blockade of the CCL3-CCR1/CCR5 and CXCL12-CXCR4 axes in an MLL-AF9-induced mouse model of acute myeloid leukemia (AML) inhibited the accumulation of TI-Tregs in the leukemic hematopoietic niche and delayed leukemia progression68. A clinical study involving FOLFOX-resistant colorectal cancer patients with high serum CCL20 levels showed that the chemotherapeutic agent, 5-FU, activates the FOXO1/CEBPB/NF-κB/CCL20 axis. This pathway subsequently recruits a large number of Tregs into tumor tissue, enhancing drug resistance. Consequently, the research team proposed the FOXO1/CEBPB/NF-κB/CCL20 axis as a potential therapeutic target for eliminating TI-Tregs69.

In summary, while current strategies targeting TNFRs and CKRs have achieved desirable Treg depletion in some preclinical studies as monotherapies or in combination, the strategies often lack tumor site-specificity and require long-term preclinical observation. Most targeting antibodies are currently in the clinical trial phase.

Other potential targets for TI-Treg depletion

Although TI-Tregs can directly impair Teffs and APCs through immunosuppressive cytokines, such as IL-10, IL-35, and TGF-β70,71, existing research indicates that IL-10 and IL-35 have crucial roles in modulating peripheral inflammation71, while TGF-β is responsible for regulating the expression of Forkhead Box P3 (FoxP3) in Tregs72. Consequently, the feasibility of strategies targeting these immunosuppressive cytokines secreted by TI-Tregs requires careful evaluation.

The evidence summarized above demonstrates that conventional strategies for targeting TI-Tregs generally have poor specificity, often leading to systemic immune dysregulation73. Maintaining the delicate balance in the abundance and function of Teffs and Tregs is paramount for preventing autoimmune pathologies. Thus, a formidable challenge in developing TI-Treg-targeting strategies lies in achieving specific depletion of TI-Tregs without compromising the antitumor functions of Teffs, while minimizing the impact on peripheral Tregs.

An in-depth exploration of the TME has revealed that, malignant and immune cells typically undergo a rewiring of energy metabolism and biosynthetic pathways that is driven by environmental stress74. Just as metabolic reprogramming is a quintessential hallmark of cancer21, TI-Tregs have evolved distinct adaptive metabolic pathways75, a biological understanding that has been shaped by a series of foundational discoveries (Figure 2). Grounded in the emerging field of immunometabolism76, this review delves into the metabolic reprogramming of TI-Tregs within the TME, postulates potential TI-Treg-specific therapeutic targets, and dissects the barriers impeding clinical translation.

Figure 2
Figure 2

Evolution of Treg metabolic research. This timeline delineates key breakthroughs in regulatory T cell (Treg) metabolism, spanning from the initial characterization of the Treg lineage-to-the contemporary understanding of metabolic reprogramming within the tumor microenvironment (TME). Highlighted milestones include the discovery of FoxP3 as a master regulator, elucidation of nutrient-sensing pathways (e.g., mTOR and AMPK), and identification of distinct metabolic profiles, such as glycolysis and lipid metabolism, that govern Treg stability and suppressive function. Created using BioRender.com.

Immunometabolism of TI-Tregs in the TME

Hypoxic microenvironment

The excessive proliferation of tumor cells and aberrant angiogenesis create a hypoxic TME, which activates hypoxia-inducible factor-1α (HIF-1α) within tumor tissues77. Most studies indicate that HIF-1α promotes the recruitment and migration of Tregs into the TME by stimulating vascular endothelial growth factor A (VEGF-A) production and/or enhancing the glycolytic rate in TI-Tregs78. Research utilizing an HIF-1α-deficient Treg mouse glioma model demonstrated reduced TI-Treg abundance in tumor tissues and improved mouse survival, suggesting that HIF-1α deficiency impairs Treg migration to tumor sites79. HIF-1α binds to Foxp3 protein via the N-terminal domain, recruiting PHDs and VHL to trigger Foxp3 ubiquitination and degradation. This binding abolishes Foxp3-mediated inhibition of the PI3K-Akt-mTOR axis, leading to glycolytic reprogramming and loss of suppressive activity in TI-Tregs80 (Figure 3).

Figure 3
Figure 3

TI-Treg stability and function are governed by a complex metabolic network that balances nutrient utilization with lineage commitment. (a) HIF-1α-driven metabolic reprogramming. ① Hypoxia triggers the accumulation of HIF-1α, which exerts effects through dual regulatory mechanisms. ② First, HIF-1α directly upregulates transcription of glycolytic enzymes, such as HK1/2 and PDK1. ③ Second, HIF-1α facilitates recruitment of the PHD/VHL complex ④ to trigger Foxp3 ubiquitination and degradation. ⑤ This loss of Foxp3 relieves the constitutive inhibition of the PI3K-Akt-mTOR axis, ⑥ which consequently fuels enhanced glycolysis and impairs TI-Treg suppressive function. (b) Lipid metabolic network: TI-Tregs utilize CD36 to uptake environmental lipids, maintaining functional stability through two parallel metabolic circuits: (b1) SCFA signaling and (b2) LCFA signaling. (b1) SCFA signaling: ① TI-Tregs utilize CD36 to uptake SCFA. ② SCFA is processed into acetate (Ace). ① To drive LCFA utilization, the energy sensor, AMPK, represses the PI3K-Akt-mTOR axis to block competing glycolysis. ② Concurrently, AMPK activates PPAR-γ. ③ PPAR-γ subsequently coordinates upregulation of CD36 and CPT1 to boost lipid uptake and transport. ④ Finally, CPT1 promotes the mitochondrial entry of LCFAs for FAO and subsequent TCA cycle flux. (c) Glucose metabolic reprogramming. ① Co-stimulation via TCR and CD28 triggers Glut1-mediated glucose uptake and initiates PI3K-Akt-mTOR signaling. ② To tailor glucose utilization for Treg stability, Foxp3 suppresses PI3K-Akt-mTOR axis, ③ thereby shifting the metabolic program toward mitochondrial OXPHOS. ④ Consequently, pyruvate is diverted away from lactate production; ⑤ instead, pyruvate fuels the mitochondrial TCA cycle to generate ATP. ⑥ This mitochondrial respiration concurrently generates ROS, which drives NFAT activation to preserve TI-Treg stability. ⑦ Beyond energy production, mitochondrial acetyl-CoA is diverted into the FAS pathway for lipid synthesis. ⑧ Simultaneously, acetyl-CoA enters the mevalonate pathway to generate cholesterol, ⑨ a process regulated by LKB1. Collectively, these biosynthetic products support membrane lipid rafts and functional maturation, reinforcing TI-Treg immunosuppressive capacity. (d) Lactate-fueled metabolic fitness. ① TI-Tregs upregulate MCT1 to efficiently uptake tumor-derived lactate. ② Internalized lactate is processed into phosphoenolpyruvate (PEP), acting as a critical metabolic hub. ③ Subsequently, this lactate-derived PEP drives mitochondrial OXPHOS to generate ATP, thereby promoting the proliferation and function of TI-Tregs within the TME. (e) Amino acid metabolism. ① TI-Tregs scavenge environmental arginine and glutamine via amino acid transporters. ② Internalized glutamine is converted into glutamate through glutaminolysis. ③ Subsequently, glutamate enters the TCA cycle to drive mitochondrial respiration. Collectively, this metabolic flexibility ensures TI-Treg persistence and robust immunosuppressive activity within the hostile tumor microenvironment. AA, amino acids; Ace, acetate; AKT, protein kinase B; AMPK, adenosine monophosphate (AMP)-activated protein kinase; α-KG, α-ketoglutarate; CCR, C-C chemokine receptor; CD28, cluster of differentiation 28; CD36, cluster of differentiation 36; CNS2, conserved non-coding sequence 2; CPT1, carnitine palmitoyltransferase-1; FAO, fatty acid oxidation; FAS, fatty acid synthesis; Foxp3, forkhead box P3; Glut1, glucose transporter 1; HIF-1α, hypoxia-inducible factor 1α; HK1/2, hexokinase 1/2; LC-FA, long-chain fatty acid; LKB1, liver kinase B1; MCT1, monocarboxylate transporter 1; mTORC, mammalian target of rapamycin complex; NFAT, nuclear factor of activated T cells; OXPHOS, oxidative phosphorylation; PDK, pyruvate dehydrogenase kinase; PEP, phosphoenolpyruvate; PHDs, prolyl hydroxylases; PI3K, phosphatidylinositol 3-kinase; PPAR-γ, peroxisome proliferator-activated receptor gamma; SC-FA, short-chain fatty acid; TCA, tricarboxylic acid cycle; TCR, T-cell receptor; TI-Treg, tumor-infiltrating regulatory T Cell; TME, tumor microenvironment; VHL, von Hippel-Lindau protein. Created using BioRender.com.

However, an alternative perspective suggests that HIF-1α can upregulate the expression of pyruvate dehydrogenase kinase 1 (PDK1) in TI-Tregs. This finding impedes the conversion of pyruvate to acetyl-CoA, inhibiting the tricarboxylic acid (TCA) cycle. Concurrently, HIF-1α upregulates various glycolytic enzymes, such as hexokinase (HK1/2), phosphofructokinase (PFKL/PFKP), phosphoglycerate kinase 1 (PGK1), and enolase (ENO1/2), promoting a metabolic shift towards glycolysis in TI-Tregs to facilitate adaptation to the hypoxic microenvironment81 (Figure 3). Consequently, the precise mechanism by which HIF-1α influences TI-Treg function and metabolism remains controversial and warrants further investigation.

Lactate metabolism reprogramming

Tumor cells primarily rely on aerobic glycolysis, known as the Warburg effect, for glucose metabolism82. This process leads to substantial accumulation of lactate, which inhibits CD8+ T and natural killer (NK) cell function21,83. In contrast, guided by the lineage-defining transcription factor, FoxP3, TI-Tregs primarily generate energy through oxidative phosphorylation (OXPHOS) and fatty acid oxidation (FAO)84. In addition to promoting this specific energy metabolism profile in TI-Tregs85, FoxP3 directly upregulates expression of the transmembrane glycoprotein, CD147, and monocarboxylate transporter 1 (MCT1) in eTregs, further mediating metabolic reprogramming in TI-Tregs86 (Figure 3).

TI-Tregs import lactate via MCT1 and convert lactate into phosphoenolpyruvate (PEP). PEP subsequently supports OXPHOS, thereby promoting the proliferation and function of TI-Tregs within the TME84 (Figure 3). Based on this finding, targeting PEP has been proposed as an immunometabolic strategy to disrupt ATP synthesis and inhibit TI-Treg proliferation87. Research indicates that MCT1 is essential for lactate uptake and maintenance of strong immunosuppressive function in TI-Tregs, whereas MCT1 appears dispensable for Tregs from non-tumor sites88. Therefore, restrictive targeting of MCT1 within tumor tissues may represent a future approach to block lactate utilization by TI-Tregs.

TI-Tregs upregulate Slc16a1 (encoding MCT1) and Ldha (a key lactate metabolism enzyme) under low or no glucose culture conditions, enhancing the capacity for lactate uptake and metabolism88. Consequently, targeting LDHA could theoretically inhibit lactate production by tumor cells via glycolysis, deprive TI-Tregs of a carbon source for OXPHOS, and alleviate the functional suppression of CD8+ T cells in high-lactate environments. However, considering that pro-inflammatory cells in the TME, such as Teffs and M1 macrophages, also utilize glycolytic pathways as part of the metabolic reprogramming89, an important question arises: would targeting LDHA also inadvertently suppress the glucose metabolism of these immune cells? Current evidence regarding this potential on-target, off-tumor effect is insufficient and requires further investigation. Similarly, the hypothesis of specifically targeting Slc16a1 to precisely block lactate uptake in TI-Tregs remains to be validated through experimental studies.

Recent research has shown a positive correlation between lactate concentration in the TME and intracellular levels of PEP, Ga2+, and nuclear factor of activated T-cells 1 (NFAT1) in TI-Tregs. Furthermore, NFAT1 promotes PD-1 expression on TI-Tregs. Based on these findings, some research groups have suggested considering lactate as a tumor-derived metabolic signal and a potential target for selectively targeting TI-Tregs86.

Lactate metabolism and immunotherapy

Previous studies have indicated that PD-1 expression on eTregs in tumor tissues is associated with treatment resistance and hyper-progression during PD-1 blockade therapy90. Research in a mouse liver tumor model demonstrated that abundant lactate promotes PD-1 expression on TI-Tregs, leading to resistance against anti-PD-1 therapy. Genetic or pharmacologic inhibition of LDHA in tumor tissues or of MCT1 in TI-Tregs reduced intratumoral lactate levels, decreased PD-1 expression on TI-Tregs, and increased the abundance of activated CD8+ T cells86. Therefore, targeting LDHA in tumors or MCT1 in TI-Tregs could, to some extent, overcome resistance to PD-1 blockade. Studies have shown that specific ablation of LDHA or MCT1 not only slows tumor growth but also synergizes with immune checkpoint blockade therapy91.

Consequently, targeting MCT1 or LDHA to impair the metabolic fitness of TI-Tregs may yield the desired therapeutic effect. However, due to the distinct metabolic properties of tumors in different organs and inter-individual heterogeneity, the long-term efficacy and potential limitations of this strategy require continued validation and observation in animal models.

Glucose metabolism

FoxP3-mediated glucose metabolic reprogramming in TI-Tregs

FoxP3 serves as a key regulator mediating the metabolic reprogramming of TI-Tregs within the TME92. FoxP3 suppresses the phosphatidylinositol 3-kinase-protein kinase B-mammalian target of rapamycin (PI3K-Akt-mTOR) signaling pathway, thereby reducing the glycolytic rate24 (Figure 3). Analysis of microarray gene expression data has revealed that the presence of FoxP3 leads to strong downregulation of glycolytic and non-glycolytic Myc target genes85. Subsequent research further elucidated that FoxP3 reprograms TI-Treg metabolism by inhibiting Myc expression and glycolysis, while simultaneously enhancing oxidative phosphorylation and increasing oxidized nicotinamide adenine dinucleotide (NAD+) levels93. FoxP3 profoundly influences the survival and functional state of TI-Tregs through transcriptional control over metabolic gene expression. Consequently, targeting FoxP3 may be considered a potential foundational strategy for eradication of TI-Tregs.

Research on glucose metabolism in TI-Tregs

TI-Tregs exhibit greater tolerance for high-lactate environments than high-glucose conditions. Elevated glucose levels in culture can impair TI-Treg function and stability because glucose uptake appears inversely correlated with the ability to maintain immunosuppressive function88. Glycolysis within the TME has a crucial role in the migration, proliferation, and immunosuppressive function of TI-Tregs94,95, and this glycolytic process is subject to regulation by multiple factors.

The PI3K-Akt-mTOR pathway is a key hub regulating glycolysis. Enhancing PI3K-Akt-mTOR signaling can increase the glycolytic rate in TI-Tregs but paradoxically interferes with proliferation and stability96,97. Conversely, inhibiting the PI3K-Akt-mTORC1 signaling pathway reduces glycolysis while enhancing OXPHOS and FAO98 (Figure 3). For example, using mTOR inhibitors to restrict glucose uptake and glycolysis in mouse B16-F10 melanoma models increased the number of TI-Tregs and strengthened the suppressive function99,100. PI3K-Akt-mTOR pathway activity is itself regulated by various upstream and downstream molecules, such as HIF-1α and AMP-activated protein kinase (AMPK)101,102. Studies have shown that metformin (an AMPK activator) suppresses mTOR activity and reduces glycolysis in TI-Tregs103. Inhibiting HIF-1α expression disrupts glycolysis and induces TI-Treg differentiation104. Using the hexokinase inhibitor, 2-deoxyglucose (2-DG), can promote TI-Treg proliferation105.

The Myc gene is another important regulator of glycolysis; Myc-overexpressing tumors exhibit accelerated glycolytic rates88. While numerous studies have indicated that glucose uptake exerts an antagonistic effect on TI-Treg proliferation and function106, recent research has confirmed that TI-Tregs can enhance mTOR activity to utilize glycolysis for meeting additional energy demands107,108. Alternatively, activation of the PI3K-Akt-mTORC1 pathway via TLR signaling increases Glut1-mediated glucose uptake and accelerates glycolysis in TI-Tregs, thereby promoting proliferation at the expense of suppressive function24. Furthermore, Tregs exhibit metabolic flexibility by utilizing different glucose metabolic pathways that depend on nutrient availability in normal versus metastatic tissues, effectively balancing glucose-lactate homeostasis.

The precise mechanisms through which glucose metabolism influences TI-Treg migration, proliferation, differentiation, and functional maintenance are incompletely understood and subject to considerable debate. Intervention strategies targeting TI-Treg glucose metabolism are still primarily in the clinical trial stage4. Specifically targeting TI-Treg glycolysis remains a promising yet prospective concept that requires more extensive investigation.

Fatty acid metabolism

Numerous studies have demonstrated that the proliferation of TI-Tregs primarily relies on FAO rather than glycolysis84,109. Both fatty acid synthesis (FAS) and FAO positively correlate with the suppressive function and stability of TI-Tregs110,111 (Figure 3). Consequently, current strategies targeting TI-Treg lipid metabolism primarily focus on inhibiting FAS and FAO processes112,113, such as modulating key enzymes and transporters involved in fatty acid metabolism. These strategies include AMP-activated protein kinase (AMPK), liver kinase B1 (LKB1), carnitine palmitoyltransferase 1 (CPT1), and the scavenger receptor, CD36114,115.

Research has shown that pharmacologic inhibition of CPT1, a key rate-limiting enzyme in FAO, can suppress TI-Treg proliferation116. Similarly, targeting CD36 safely and effectively blocks lipid uptake specifically in TI-Tregs, inhibiting proliferation and differentiation within the tumor tissues without affecting systemic Treg populations117. Therefore, combining anti-CD36 therapy in mouse models with anti-PD-1 blockade has been shown to prevent the onset of autoimmune diseases113.

Amino acid metabolism

Tryptophan and arginine are two essential amino acids involved in immune regulation. IDO, a rate-limiting enzyme, catabolizes tryptophan into kynurenine and 3-hydroxyanthranillic acid (3-HAA), subsequently promoting Treg proliferation in vitro and facilitating Treg migration into the TME118 (Figure 3). The tryptophan metabolite, kynurenine, binds to the aryl hydrocarbon receptor, inducing tolerogenic dendritic cells (DCs) and promoting the generation and function of TI-Tregs119. Arginine deficiency impairs TI-Treg proliferation120. However, arginine can also stimulate IL-10 production by inducing DNA methylation in the IL-10 promoter region, consequently promoting TI-Treg generation121. Increased glutamate concentration within the TME promotes TI-Treg infiltration and weakens the anti-tumor immune response122.

Thus, amino acid metabolism is crucial for the proliferation and differentiation of TI-Tregs. Although various IDO inhibitors have been developed, such as the secondary sulfonamide compound (Compound 5d), GDC-0919, INCB-024360, and NLG802, none have been approved for clinical use123. Therefore, a proposed strategy involves limiting the availability of amino acids essential for TI-Treg metabolism and inhibiting the production of their metabolites, thereby interfering with TI-Treg proliferation and effector functions.

In summary, TI-Tregs exploit metabolic intermediates in the TME via metabolic reprogramming, allowing for the flexible adaptation of macronutrient uptake and utilization (Figure 3). This metabolic flexibility is critical for proliferation, differentiation, and functional maintenance. Nevertheless, the precise mechanisms governing these processes remain a subject of debate and need to be better defined. While various therapeutic strategies targeting TI-Tregs have been postulated and investigated in preclinical and clinical trials (Table 1), highly effective agents have yet to successfully transition into clinical practice. Consequently, considering the complex crosstalk within the TME, the identification of specific therapeutic targets on TI-Tregs requires continued exploration.

View this table:
Table 1

Therapeutic strategies targeting Tregs in preclinical and clinical trials (partial list)

Conclusions

While ICB represents a paradigm shift in oncology, the clinical utility is frequently compromised by the paradoxical enhancement of Treg activity. Furthermore, systemic targeting of Tregs risks inducing severe autoimmunity, in which the resultant adverse events may negate clinical gains. Consequently, dissecting the specific metabolic adaptations of Tregs within the TME is essential for designing precision therapies against TI-Tregs. However, our current understanding of Treg metabolic adaptations within the TME remains limited. Specifically, the intricate metabolic-functional axis involving glycolysis and regulation of HIF-1α/FoxP3 expression warrants deeper exploration. Thus, the development of strategies for the precise and selective targeting of TI-Tregs continues to represent a significant challenge in the field.

Conflict of interest statement

No potential conflicts of interest are disclosed.

Author contributions

Conceived and designed the analysis: Na Li.

Collected the data: Na Li.

Contributed data or analysis tools: Na Li, Dexue Tian.

Performed the analysis: Na Li, Dexue Tian.

Wrote the paper: Na Li.

  • Received October 22, 2025.
  • Accepted January 23, 2026.

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