Mitochondria are hubs of cellular metabolism, including glucose, amino acid, and fatty acid metabolism (40). As the main pathway of energy metabolism in tumor cells, glycolysis is crucial for the proliferation and functional activities of immune cells (41). Upon T cell activation, there is a shift in their metabolism from a quiescent state, primarily relying on OXPHOS, to an activated state characterized by increased glycolysis, which allows for the swift production of ATP and metabolic intermediates necessary for cell proliferation and effector molecule synthesis (21, 22). It has been reported that the naïve T cells rely on OXPHOS to maintain energy requirements, while activated T cells consume a large amount of glucose through aerobic glycolysis to exert anti-tumor effects (42, 43). HIF-1α is required for effector states in CD8+T cells, and the loss of HIF-1α in CD8+T cells reduces tumor invasion and tumor cell killing and alters tumor vascularization (44). Mitochondrial dysfunction causes redox stress, which inhibits proteasomal degradation of Hypoxia-inducible factor-1α (HIF-1α) and promotes transcription and metabolic reprogramming of Tpex cells to become exhausted T cells (45). In addition, MYC plays a key role in regulating the response of HIF-1α to hypoxia, and the MYC signaling pathway is uncoupled from the increased transcription of HIF-dependent glycolytic genes in glycolytic flux during hypoxia (46). In CD4+T cells, the loss of HIF-1α or HIF-1α and HIF-2α also impairs essential functions during antibody response. Glycolysis increases the expression of T helper cytokines, and HIF promotes glycolysis in T helper cells through TCR or cytokine stimulation (47). Solute carrier (SLC) plays an important physiological function in cells. Increased glucose uptake mediated by GLUT1 and GLUT3 transporters maintains T cell activation and promotes differentiation (48). After entering the site of inflammation, CD4+ and CD8+ T cell subsets internalize high levels of lactic acid via SLC15A2 and MCT1 (SLC16A1), respectively (49, 50). Macintyre AN et al. ‘s findings suggest that Glut1 deficiency leads to impaired glucose uptake and glycolysis within CD4 T cells, thereby reducing the survival and differentiation ability of T effector cells, as well as the ability to induce inflammatory diseases in vivo. However, the function of Tregs does not appear to be affected by the Glut1 defect (48). In addition, metabolites produced during glycolysis also participate in the activation and effector function of T cells through other ways. Teff cells up-regulate specific glycolytic pathways to achieve rapid proliferation and play anti-tumor effect, including aerobic glycolysis, pentose phosphate pathway (PPP), hexosamine biosynthetic pathway (HBP), and TCA cycle support (51). CD8 T cells are an important part of human adaptive immune response, and changes in glycolysis have important effects on their activation and function. Activation of CD8 T cells by TCR leads to the transfer of cellular metabolic level to glycolysis, while the synergistic stimulation of CD28 further increases the glycolysis level of CD8 T cells to support subsequent proliferation and differentiation (52). The induction of high glycolytic activity is conducive to the differentiation of CD8 T cells into effector cells, but it can seriously impair the survival ability of Tmem cells (53, 54).

In addition to glycolysis, the massive proliferation of activated T cells relies primarily on amino acid metabolism to support protein and nucleotide synthesis (55). Glutamine metabolism supplies carbon and nitrogen necessary for the synthesis of amino acids, nucleic acids, and lipids. The lack of glutamine inhibits T cell proliferation and cytokine production, which implies that the restoring high levels of glutamine to the TME can enhance T cell killing of tumor cells (56).

Besides, arginine is a precursor in the biosynthesis of many macromolecules, including proteins, creatine, and polyamines (57–59). As arginine deprivation can lead to cell cycle arrest, arginine is important for T cell proliferation (60). Elevated L-arginine levels induced a shift from glycolysis to oxidative phosphorylation in activated T cells and promoted the production of central memory-like cells with higher viability. Intracellular L-arginine concentration can directly affect the metabolic adaptability and viability of T cells, which also reveals the importance of its anti-tumor response (61).

The presence of extracellular methionine influences the epigenetic programming responsible for shaping the destiny of CD8+ T cells and synergizes with serine (which can be synthesized internally from glucose or obtained externally) to stimulate one-carbon metabolism (62–64). Lysine catabolism can affect CD8+ T cells to reprogram tumor immunity via histone crotonylation (65). Amino acids, particularly arginine and leucine, signal to allow TCR-induced mTORC1 activation and subsequent changes in mitochondrial metabolism in Treg cells via RagA/B and Rheb1/2 (66). SLC1A5 or SLC38A1 cotransports glutamine and leucine exchanged via the SLC7A5-SLC3A2 complex can promote mTORC1 activation through direct and indirect mechanisms, thereby regulating T cell metabolism (67). Tryptophan is an essential amino acid and factor in determining the strength and effectiveness of T cell responses in TME. Tryptophan can directly activate cytoplasmic transcription factor-aryl hydrocarbon receptor (AhR) by producing kynurenine (Kyn) catalyzed by indoleamine 2,3-dioxygenase (IDO) (68). T cells can regulate Tumor repopulating cells (TRC) that can induce CD8+ T cells to express PD-1 through Kyn uptake and AhR activation through IDO-Kyn-AhR pathway (68). Besides, glutaric acid, a key metabolite produced during the breakdown of tryptophan and lysine within T cells, regulates T cell differentiation by altering epigenetic and energy metabolism (69).

Lipids are divided into a variety of subtypes based on their structural/biological characteristics, including fatty acids (FAs), phospholipids, cholesterol, triglycerides, etc. In TME, lipid metabolism, as an important energy source and one of the significant components of cell membrane, is closely related to T cell proliferation and function (70). T cell senescence driven by malignant tumor cells and TreGs is a common feature in cancer development. Senescent T cells have active glucose metabolism, but their lipid metabolism is unbalanced (71). Through experiments in mouse models of melanoma and breast cancer, Liu X found that the inhibition of phospholipase A2-IVA can reprogram lipid metabolism of effector T cells and prevent T cell aging. Oxidized cholesterol is enriched in the tumor microenvironment, and oxidized cholesterol inhibits SREPB2 pathway from activating LXR pathway, thus resulting in cholesterol deficiency and T cell dysfunction (72). Moreover, FAO is involved in the generation and functional maintenance of Tmem cells. Saibil et al. proved that, as the energy source, FAO enables Tmem cells to respond to antigen stimulation in a timely manner, which is conducive for maintaining the normal function of Tmem mitochondria and long-term cell survival (73). FAO regulates the balance between Teff and Treg cells (74). However, it should not be ignored that while Tregs do depend on mitochondrial function, it is not necessarily fatty acid oxidation. For example, Chapman et al. discovered that mTOR plays an important role in coordinating transcriptional and metabolic programs in activated treg subpopulations, thereby mediating tissue homeostasis processes (75). Weinberg et al. demonstrated that Treg cells require mitochondrial complex III to maintain immune regulatory gene expression and suppressive function (76). Furthermore, mitochondrial transcription factor A (Tfam) is essential for mitochondrial respiration and the control of mitochondrial DNA replication, transcription, and packaging. The loss of Tfam in Treg affects Treg homing and stability, thus leading to tissue inflammation in colitis, but enhances tumor rejection, which reveals the key role of TFAM-mediated mitochondrial respiration in regulating inflammation and anti-tumor immunity in Tregs (75, 77). Saravia et al. revealed that the transcriptional regulatory factor c-Myc can coordinate immune homeostasis by coordinating treg accumulation, transitional activation, and metabolic programming (78). However, in fact, several recent studies showed that Cpt1a is dispensable for Treg generation or function in vivo. For example, Raud et al. illustrated that the ACC2/Cpt1a axis is largely indispensable for the formation of Teff, Tmem or Tregcell, and the effects of etomoxil on T cell differentiation and function are independent of Cpt1a expression (79). This finding provides data support that metabolic pathways other than LC-FAO can promote Tmemor treg differentiation. Besides, Treg-specific deletion of Cox10, rather than FAO’s rate-limiting enzyme Cpt1a, has been confirmed to promote oxidative phosphorylation, thereby leading to impaired treg function and maturation (78). What’s more, the lipid metabolism reprogramming of CD8+ T cells can affect the biology of tumor cells (80). Yang W et al. identified cholesterol esterification enzyme (ACAT1) as a metabolic checkpoint that regulates tumor immune response, and inhibition of its activity can increase the level of free cholesterol on CD8+ T cell membrane, thereby enhancing the tumor-killing ability of CD8+ T cells (81). The main mechanism is that the plasma membrane cholesterol level of CD8+ T cells increases significantly, which helps the efficient formation of T cell antigen receptor clusters and immune synapses. Moreover, studies have confirmed that the combination of ACAT inhibitor Avasimibe and PD-1 antibody can further improve the effectiveness of tumor immunotherapy. Moreover, Fan J et al. found that mitochondrial ACAT1 and SIRT3 are upstream acetyltransferase and deacetylase of PDHA1 and PDP1, respectively, and knockdown of ACAT1 can weaken tumor growth (82). These studies suggest the potential of ACAT1 as a target for anti-cancer drugs. Overall, different states of T cells are controlled by multiple metabolic programs (83, 84) ( Figure 1 ). The metabolic reprogramming of T cells is an essential component of the immune response. Understanding and manipulating T cell energy metabolism has significant implications for developing novel immunotherapies and enhancing immune responses against tumors.

Hypoxia in the TME has a unique two-sided effect on immune cell function (85). Under hypoxic conditions, multiple oxygen-independent signals, including those present in T cells, increased hypoxia-inducible factor (HIF) activity (86). After activation via oxygen-independent pathways, T cells depend on HIFs to sustain glycolytic metabolism. For instance, Oestreich et al. reported that following T cell activation, decreased interleukin (IL)-2 exposure lead to elevated B-cell lymphoma 6 (Bcl-6) expression, which directly inhibited glycolytic genes regulated by HIF-1α and c-myc. This mechanism suppresses glycolytic metabolism and effector function, and consequently influences the fate of T cells in a microenvironment-dependent manner (87). A previous investigation on Foxp3-regulatory CD4+ T cells revealed the involvement of HIF-1α in maintaining a glycolytic metabolic shift in CD4+ T cells, when it was activated and cultured in vitro with IL-27 (88), which suggested the crucial role of HIF-1α in modulating CD4+ T cell metabolism. The HIF-1α expression in CD8+ T cells promotes glycolytic metabolism, thus leading to enhanced proliferation and effector functions of CD8+ T cells (44, 89). Compared with normoxic T cells, hypoxic CD8+ T cells increased the packaging of granzyme B into particles and cleared B16 tumors more effectively in mice (90). This adaptive metabolic transformation and functional enhancement contribute to the anti-tumor effects of CD8+ T cells in a hypoxic environment. In a CRC cell model, it has been observed that hypoxia enhances the CD8+ T cell activity and promotes IFN-γ expression (91).

To achieve “metabolic equilibrium,” tumor cells not only consume important nutrients but also produce toxic metabolic waste to further impact the differentiation of CD8+ T cells and impair T cell function. Among these, lactate accumulation has attracted considerable attention. Owing to the aerobic glycolytic activity of tumor cells, lactate accumulates in the TME, and high lactate concentrations directly regulate the effector function of CD8+ T cells (92). Activated T cells primarily produce ATP and biomacromolecules via aerobic glycolysis. To maintain a high glycolytic rate, CD8+ T cells export lactate through Monocarboxylate Transporter 1 (MCT1). The transport activity of MCT1 is mainly regulated by the lactate concentration gradient in the cell membrane. However, lactate accumulation in the TME disrupts MCT1-mediated lactic acid export from CD8+ T cells, and further induces an inhibitory tumor-infiltrating (TIL) CD8+ phenotype (92). Robert et al. also demonstrated that the build-up of lactic acid generated by CRC cell metabolism and the resulting acidic environment could repress glycolysis and impair T cell functionality (93). Additionally, lactic acid can induce the upregulation of CXCL10, which facilitates the attraction of CD4+ T cells to the metastatic site and triggers receptor activator of nuclear factor-κB-ligand (RANKL) production, thereby promoting CRC bone metastasis (94, 95).

Dysregulation of the gut microbiota is a crucial factor in both cancer onset and immune system modulation, which ultimately affectes the efficacy of immunotherapy (96). In mouse models, a microbial mixture could boost anticancer immunity by stimulating the production of IFN-γ-producing cytotoxic T cells (CTCs) within tumor tissues (97). Escherichia coli, Firmicutes, and Bacteroides fragilis have been found to promote the migration of T cells into CRC tissues by upregulating the expression of chemokines involved in T cell recruitment (98). However, colibactin-producing Escherichia coli can impair the infiltration of CD3+ and CD8+ T cells into the CRC, thus resulting in tumor resistance to immunotherapy (99). Moreover, the colonization of Bifidobacterium in the intestine can result in changes in the composition of the gut microbiota and increase the suppressive function of Treg cells by promoting mitochondrial activity, which indicates the crucial role of gut microbiota in the metabolic reprogramming of T cells (100).

What’s more, the gut microbiota generates multiple metabolites that can interact with host tissues and the immune system, which exertes a significant influence on T cell development and function (101, 102). Intestinal immune homeostasis can be maintained by Treg cells, and microbial bile acid metabolites are vital for generating colonic Treg cells and suppressing intestinal inflammation (103–106). Bacterial production of short-chain fatty acids (SCFAs), such as butyrate, can alleviate dextran sulfate sodium and clostridium difficile induced colitis by preventing Th17 through activation of SIRT1/mTOR (107). SCFAs, as the substrate for β-oxidation, can elevate the mitochondrial mass and glucose transporter protein type 1 (GLUT1) expression as well as stimulate OXPHOS and glutaminolysis instead of glycolysis in activated CD8+ T cells. Not only that, butyrate can promote cell metabolism and enhance the memory potential of activated CD8+ T cells. In this process, butyrate decoups the tricarboxylic acid cycle from glycolytic input to CD8+ T cells, which prefertionally provides fuel for oxidative phosphorylation through ongoing glutamine utilization and fatty acid catabolism (83). SCFAs, as the substrate for β-oxidation, can elevate the mitochondrial mass and glucose transporter protein type 1 (GLUT1) expression as well as stimulate OXPHOS and glutaminolysis instead of glycolysis in activated CD8+ T cells (108). The gut microbiota-derived metabolite butyrate modulates the effector function of CD8+ T cells (83). Additionally, pentanoate, a subdominant type of SCFA, was found to directly affect CD4+ T cell metabolism. Pentanoate stimulated glycolysis and increased acetyl-CoA levels in Th17 cells (109). Isoallolithocholic acid (isoalloLCA), a secondary bile acid, augments OXPHOS in CD4+ T cells, which is indicated by the elevated oxygen consumption and mitochondrial membrane potential (104). As a key metabolite produced by glycolytic metabolism of glucose molecules, lactic acid prevents the upregulation of activated T nuclear factors in T cells and NK cells, thus resulting in reduced IFN-γ production. As a potent inhibitor of T and NK cell function and survival, lactic acid can cause tumor immune escape (110). Besides, lactate can increase the dryness of CD8+T cells and enhance anti-tumor immunity (111). In addition, studies have shown that lactic acid is an active checkpoint for Treg cell function, and it can up-regulate PD-1 expression in highly glycolytic TME (112). Treg cells up-regulate pathways involved in the metabolism of lactic acid. Lactate uptake is essential for the function of peripheral treg cells, but it requires intratumoral uptake, thereby resulting in slower tumor growth and increased response to immunotherapy (50).