The oxidative decomposition of glucose provides the primary energy source for cells. Normal cells acquire energy by thoroughly oxidizing glucose to CO₂ and water under aerobic conditions, whereas tumor cells prefer to convert glucose into lactate via glycolysis, even under oxygen-sufficient conditions. This is referred to as the Warburg effect (3). Compared with oxidative phosphorylation (OXPHOS), aerobic glycolysis results in inefficient, but rapid, ATP production, accompanied by the production of intermediates and metabolites that act as major raw materials for cellular biosynthesis (4, 5). Collectively, aerobic glycolysis is conducive to the rapid growth and proliferation of tumor cells. Notably, the Warburg effect is not an exclusive feature of tumor cell metabolism, because cells in different tumor tissue regions preferentially utilize distinct metabolic pathways depending on the TME conditions and nutrient availability (6). Previous research has shown that oxygenated tumor cells produce large amounts of ATP through the oxidative phosphorylation of glucose, whereas hypoxic tumor cells mainly utilize glycolysis to supply energy and produce lactate for oxygenated tumor cells to fuel oxidative metabolism (7). This coupled metabolic pattern is of great significance for tumor cell growth and proliferation.

Glucose deficiency is a striking feature of the TME. The rapid proliferation of tumor cells enhances glucose uptake through the overexpression of the glucose transporters, GLUT1 and GLUT3, to relieve glucose dependence, resulting in glucose deficiency in the TME. It has been suggested that upregulated expression levels of glucose transporters in tumor cells is closely associated with poor cancer prognosis (8). Increased oxygen consumption resulting from tumor cell hyperproliferation creates a hypoxic microenvironment that contributes to tumor invasion and metastasis (9). In addition, both aerobic glycolysis and glutamine catabolism in tumor cells produce large amounts of lactate, rendering the TME acidic (10). Although most cancer-metabolism-related studies have considered lactate as a metabolic waste product in the Warburg effect, recent studies have suggested that lactate is a potential fuel (11).

Lipids are another abundant metabolite in the TME, and their accumulation is closely related to immune cell dysfunction and tumor cell survival (12). Amino acids are primarily involved in cellular component synthesis and energy metabolism (such as the TCA cycle), which, along with their metabolites, contribute to various effects on antitumor immune responses and tumor growth in the TME (13). Moreover, the high accumulation of nucleosides (especially ATP) in the TME contributes to tumor immune escape (14, 15).

In general, the characteristics of the TME, including hypoxia, acidification, lack of nutrients (such as glucose and amino acids), and massive accumulation of immunosuppressive metabolites (such as lactate, lipids, and nucleosides), effectively promote tumor progression and influence antitumor immune responses.

Immune cells in the TME are divided into three categories based on their functions in tumor cells. The first group comprises immune cells with antitumor effects, mainly CD8⁺ T cells, CD4⁺ Th1 cells, natural killer (NK) cells, and dendritic cells (DCs). The second group consists of tumor-promoting immune cells, including CD4⁺CD25⁺ T cells (Tregs), myeloid-derived suppressor cells (MDSCs), and mast cells. Additionally, highly heterogeneous macrophages and neutrophils exert distinct immune functions via phenotypic changes in different local tissue microenvironments.

T cells are essential immune cells that can differentiate into CD8⁺ T cells with cytotoxic activity and CD4⁺ T cells with helper functions. CD8⁺ and CD4⁺ T cells have multiple cell subtypes that play multifaceted roles in tumorigenesis according to the different cytokines they produce ( Table 1 ). The infiltration of CD8⁺ T cells and CD4⁺ Th1 cells at the tumor site is a hallmark of a favorable tumor prognosis (51), due to their production of the cytokines IFNγ and TNFα, which can effectively induce the cell cycle of tumor cells to arrest in the G1/G0 phase (20, 52). As the most powerful antigen-presenting cells, DCs play key roles in innate and adaptive immunity, as they can effectively activate resting T cells to transform them into cytotoxic T lymphocytes to promote an antitumor immune response (53). NK cells are also an integral part of the antitumor immune response. They exert cytotoxic effects on their target cells by forming immune synapses and directionally secreting lysed particles, such as perforin and granzyme (54).

Tregs inhibit autoimmune reactions and maintain immune homeostasis in vivo (55). Tregs expressing the transcription factor Foxp3 are closely associated with a poor prognosis in multiple cancers (56). Similarly, Th2 and Th17 cells contribute to tumor occurrence and development (51). MDSCs are myeloid-derived cells, including polymorphonuclear MDSCs (PMN-MDSCs) and mononuclear MDSCs (M-MDSCs) (57). Tumor-infiltrating MDSCs exert tumor-promoting effects by inducing the generation of immunosuppressive Tregs and M2-type macrophages and inhibiting T cell activation (58). Mast cells, also known as basophils, are derived from myeloid cells and they secrete several bioactive molecules with tumor-promoting functions, such as angiogenic factors and matrix metalloproteinases (59). In addition, IL-33-activated mast cells promote tumor outgrowth by secreting macrophage chemokines to facilitate tumor-associated macrophages (TAMs) recruitment to tumor sites (60).

Macrophages and neutrophils perform distinct functions through environment-dependent phenotypic transformations. It is generally believed that macrophages mainly fall into two categories: type 1 (M1) and type 2 (M2) macrophages. M1 macrophages with proinflammatory and tumor-suppressive effects primarily rely on aerobic glycolysis for their energy supply, whereas M2 macrophages utilize fatty acid oxidation (FAO) to fuel mitochondrial OXPHOS, which is beneficial for repairing tissues, maintaining metabolic homeostasis, and enhancing tumor progression (61). Tumor cells recruit TAMs with an M2-like phenotype to the tumor microenvironment to disrupt immune surveillance (62). Similar to TAMs, tumor-associated neutrophils (TANs) can be divided into an N1 phenotype with antitumor activity and an N2 phenotype with protumor activity. The immunosuppressive cytokine TGF-β, which is overexpressed by tumor cells, can induce TAN polarization toward the N2 phenotype (63).

According to the “Comprehensive Classification System for Lipids” published by the International Lipid Classification and Nomenclature Committee in 2005, lipids can be divided into the following eight categories: fatty acyls, glycerolipids, glycerophospholipids, sphingolipids, sterol lipids, prenol lipids, saccharolipids, and polyketides (96). Since lipids are cellular nutrients and signaling molecules, functional changes in lipid transporters are key modulators of the immune response. Several transmembrane and intracellular transporters mediate lipid transport ( Figure 1 ). The CD36 transporter and fatty acid transport proteins (FATPs) are major lipid uptake transporters. Lipids are ingested intracellularly by the CD36 transporter in the form of low-density lipoprotein (LDL), very-low-density lipoprotein (VLDL), and fatty acids (61, 70). The FATP family, which is composed of six members (FATP1-6), mediates exogenous fatty acid uptake with different tissue expression patterns (97). Fatty acid binding proteins (FABPs) are a family of small proteins that act as intracellular fatty acid transporters (98), while ABCA1 and ABCG1 can synergistically mediate intracellular cholesterol efflux (99).

As a vital nutrient that supports energy production and biomass synthesis in cells, glucose is mainly transported into cells through GLUTs, a family of glucose transporters encoded by the SLC2A gene family (121). Activated CD4⁺ T cells support metabolic reprogramming toward aerobic glycolysis by upregulating GLUT1 expression levels to rapidly proliferate and differentiate into immune-promoting effector T (Teff) cells and immune-inhibiting Treg cells (122). Decreased GLUT1 expression levels in T cells from cancer patients may be closely related to the expression levels of the inhibitory receptors, PD-1 and TIM3 (73, 74, 123). A study of lung squamous cell carcinoma identified GLUT3 as the main glucose transporter in immune cells of the TME (124). Increased glucose uptake by GLUT3 in T cells inhibits GLUT3-mediated glucose uptake by cancer cells, indicating that immune cells with high GLUT3 expression levels promote effective antitumor immunity (124). Teff cells selectively depend on the glucose transporter GLUT1 for proliferation and inflammatory responses (122, 125). In addition, Tregs with increased GLUT1 expression levels and glycolytic reactions in the TME are functionally unaffected by GLUT1 deficiency, possibly because the energy supplementation pathway involves lipid metabolism (122, 126). Compared to normal neutrophils, neutrophils with pro-tumor functions exhibit higher GLUT1 expression levels and glucose metabolism (127). Similarly, TDE-induced macrophages achieve metabolic reprogramming by increasing the expression levels of GLUT1, HIF1-α, and lactose dehydrogenase A, which polarizes TAMs toward protumor phenotypes (79).

Monocarboxylate transporters (MCTs) belong to the SLC solute carrier family and comprise 14 members. MCT1–4 are proton-coupled monocarboxylate transporters capable of mediating the bidirectional transport of lactate, driven by a transmembrane concentration gradient (128). MCT1 and MCT4 are the most extensively studied monocarboxylate transporters involved in human cancers. MCT1 plays a major role in lactate uptake by glycolytic cells, whereas MCT4, which has a low affinity for lactate, is not easily saturated by high intracellular lactate levels and promotes lactate efflux in glycolysis-dependent cells, such as tumor cells (128, 129). High expression levels of MCT1 and MCT4 have been observed in many types of tumor cells (128). The Na-coupled transporters SMCT1 (SLC5A8) and SMCT2 (SLC5A12) also participate in lactate transport (129, 130).

Excess lactate accumulation in the TME inhibits the antitumor effects of immune cells. For activated T cells, increased lactate in the TME leads to an impaired lactate efflux function of MCT1, thus affecting glycolysis and the immune function of cytotoxic T cells (80). For NK cells, the downregulation of MCT4 expression levels in tumor cells can effectively restore their tumor-killing function by reversing the immunosuppressive TME (131). Conditions of high lactate concentration affect the antigenic phenotype and functional activity of monocyte-derived DCs, and induce MCT1 expression in plasma cell-like dendritic cells (pDCs), thereby facilitating tumor cells to evade immune surveillance (132, 133). Moreover, lactate inhibits the TLR stimulation response and IFN-α secretion through MCT1-mediated intracellular lactate transport and promotes pDCs to induce Tregs (133). Tregs with high MCT1 expression levels upregulate PD-1 expression and maintain their immunosuppressive activity in the glucose-deficient TME (82, 134). Additionally, lactate facilitates tumor immune escape by upregulating MCT1 expression levels in macrophages, thereby enabling M2 macrophage polarization (135, 136). Increased MCT4 expression levels in macrophages enhances lactate efflux, which is necessary for macrophage activation, glycolysis, and inflammatory responses (137).

To date, there has been no detailed investigation of the changes in SMCT expression levels in immune cells. It has been proposed that lactate accumulation upregulates SMCT2 expression levels in CD4⁺ T cells to enhance lactate uptake and the production of the proinflammatory cytokine IL-17, resulting in decreased glycolysis, cell activity, and migration (81, 138). DCs and macrophages also express SLC5A8 and SLC5A12, but they do not appear to exert a lactate transport function (130, 139).

Amino acids are involved in a series of complex physiological processes, such as protein synthesis, metabolism, and signal transduction. There are three major classes of amino acid transporters in the SLC superfamily. Based on their properties, amino acid transporters can be divided into neutral, basic, and acidic types. Depending on whether the transport process requires coupling with Na⁺, they can be further divided into Na⁺- and non-Na⁺-dependent transporters (13). When comprehensively considering substrate specificity and transport mechanisms, they can be further divided into multiple systems, such as A, N, ASC, B, L, T, x_c ⁻, and y⁺ (140). The relationship between amino acids and their transporters is not a one-to-one relationship ( Figure 2 ), making research targeting amino acid transporters more challenging (13).

Equilibrative nucleoside transporters (ENT1–4) encoded by the SLC29 family and condensed nucleoside transporters (CNT1-3) encoded by the SLC28 family are the major nucleotide transporters in the human body. ENTs have been implicated in the bidirectional transport of various purines and pyrimidines to maintain intracellular and extracellular nucleoside homeostasis. CNTs mediate the unidirectional uptake of nucleosides in an Na⁺- and H⁺-coupled manner (191, 192). Nucleoside transporters play a central role in transporting nucleosides, nucleobases, and nucleoside analogs, with effects on cell metabolism and signal transduction (192–194). Several studies have suggested that decreased ENT1 and CNT1 expression levels in tumor cells may be associated with drug resistance (192, 193, 195, 196). In addition, the RFC1 transporter encoded by SLC19A1 mediates the uptake of the immune transmitter cGAMP into monocyte-derived U937 cells to elicit antitumor immune responses via immune cell recruitment. However, whether other immune cells utilize this mechanism to achieve cGAMP uptake requires further investigation (197).

Hypoxia is a common feature of the TME, with inhibitory effects on cellular ENT1 expression (198–200). For example, nucleotide metabolic enzymes CD73 and CD39, expressed by immune cells, are upregulated under the regulation of HIF1-α. This leads to adenosine accumulation in the TME, which negatively affects the immune activity of Teff cells (198, 199, 201). In mice with inflammatory diseases, the ENT1-targeted drug decitabine selectively depletes Teff cells with high ENT1 expression levels and promotes the proliferation of immunosuppressive Treg cells, which may be one of the mechanisms responsible for immune tolerance (202). Macrophages simultaneously express ENTs and CNTs, and selectively express specific nucleoside transporters according to the requirements related to their growth, development, and metabolism, with regulators including lipopolysaccharide, TNF-α, IFN-γ, and M-CSF (203, 204).

The irreversible CD36 inhibitor sulfo-n-succiniminooleate (SSO) inhibits the uptake of oxidized low-density lipoprotein by macrophages (205). Experimental studies in mice have shown that the CD36-neutralizing antibodies FA6.152 and JC63.1 hold promise for inhibiting cancer cell metastasis in various cancer types (206).

Lipofermata and grassofermata specifically inhibit FATP2-mediated fatty acid transport and cytotoxic reactions caused by excessive fatty acid accumulation (106, 207). Moreover, FATP2 inhibitors, in combination with checkpoint inhibitors, alleviate the suppressive activity of MDSCs against T cells and significantly enhance antitumor immune responses (105, 106). Lipofermata may also be exploited to inhibit FATP1 because of the similarity between FATP1 and FATP2, which contributes to the effective inhibition of FATP1-mediated fatty acid uptake, thereby reducing melanoma cell proliferation (208). However, lipofermata shows no obvious therapeutic effects in tumor-bearing mice owing to its short half-life (208). Pharmacological inhibitors of FABP4, such as tamoxifen and BMS309403, effectively inhibit tumor progression (209–211). The chemical inhibitor SBFI26 restricts tumor proliferation by targeting FABP5-PPARγ-VEGF signaling (212). High FABP5 expression levels confer enhanced antitumor activity to macrophages. The small-molecule compound EI-05, identified by Rao et al., significantly increase FABP5 expression levels in macrophages and inhibits breast tumor growth in mice (213).

The ABCA1 transporter is also a potential target for tumor treatment. ABCA1 suppresses tumor growth by mediating cholesterol efflux in tumor cells to promote cell death (214, 215). Missense mutations in ABCA1 contribute to tumor progression in patients with chronic myelomonocytic leukemia (216). The tumor suppressor P53 induces ABCA1 expression, and loss of P53 or ABCA1 promotes liver tumor cell proliferation in mice (217). As the target gene of the nuclear receptor LXR, ABCA1 expression can be increased by LXR activation. Therefore, the LXR agonists T0901317 and GW3965 play crucial roles in the anti-proliferative effects on tumor cells (218). LXR agonists combined with first-line therapeutic drugs for melanoma, such as dacarbazine, vemurafenib, and anti-CTLA-4 antibodies, improve the clinical efficacy of monotherapies (219). Similarly, the combination of GW3965 and gemcitabine exhibits a more significant antitumor effect than two single-agent treatments on pancreatic cancer cell lines (220).

Treatments targeting glucose transporters mainly include drug therapies targeting GLUT1 and those providing RNA interference. Compound STF-31, identified by Chan et al., exhibits synthetic lethality in cancer cells with high GLUT1 expression levels and glycolysis dependence (221). WZB117, a small-molecule inhibitor, exerts anticancer effects by reducing GLUT1 expression levels, intracellular ATP levels, and glycolytic enzyme levels in tumor cells (222). BAY-876 is a highly selective inhibitor of GLUT1 with favorable pharmacokinetic properties both in vitro and in vivo and it exhibits potent antitumor effects against a variety of solid tumors (223–226). Polyphenols, such as resveratrol, hesperetin, catechin, and quercetin, also possess antitumor functions by reducing GLUT1 mRNA and protein expression levels in tumor cells (227). The growth of tumor cells treated with an anti-SLC2A1 short hairpin RNA (shRNA) is markedly suppressed (228). Furthermore, an shRNA targeting GLUT1 enhances cisplatin sensitivity in head and neck cancer cells (229). Collectively, RNA combined with chemotherapeutic drugs is expected to result in improved therapeutic effects against cancer. Notably, in addition to GLUT1, tumor cells upregulate GLUT3 expression levels under conditions of glucose deprivation. Therefore, drugs specifically targeting GLUT1 may be insufficient to inhibit tumor growth and may require high concentrations to elicit therapeutic effects. These issues can be overcome by a novel pan-GLUT inhibitor, Gluor, which targets the glucose transporters GLUT-1, GLUT-2, and GLUT-3, with antitumor effects at nanomolar concentrations. However, detailed investigations of the effect of Gluor in vivo are limited (230, 231).

As the predominant lactate transporters in tumor cells, MCT1 and MCT4 prevent intracellular acidification and maintain normal tumor cell growth. Consequently, MCT inhibitors have great potential for clinical applications in antitumor treatments. α-Cyano-4-hydroxycinnamate (CHC) is a selective and reversible inhibitor of MCT1 that can significantly inhibit tumor growth and reverse hypoxic conditions in the TME (7). Choi et al. effectively inhibits tumor growth by reducing MCT4 expression levels in tumor-bearing nude mice treated with an MCT4-targeting antisense oligonucleotide (MCT4 ASO) (232). Various potent MCT1 inhibitors have been reported, including SR13800, AZD3965, BAY-8002, and 7ACC2 (233). AZD3965 is an orally bioavailable MCT1 inhibitor in phase I clinical trials that effectively increases T cell infiltration, reduces lactate efflux from tumor cells, and reverses the immunosuppressive microenvironment of solid tumors (234). Moreover, syrosingopine has dual inhibitory effects on MCT1 and MCT4. In combination with metformin, which inhibits oxidative phosphorylation, sylrosiglitazone induces significant cytotoxic reactions and reduces the effective concentration of metformin (235)

Overexpression of CD98, an integral subunit of system x_c ⁻, is often closely associated with poor prognosis in many cancers. The humanized monoclonal antibody IGN523, which targets CD98, has been reported to have significant antitumor activity, and a phase I clinical trial of this antibody in patients with acute myeloid leukemia is currently underway (236). xCT, another functional subunit of the x_c ⁻ transport system, affects intracellular redox homeostasis by regulating GSH metabolism. The transcription factor Nrf2 controls the antioxidant pathway in eukaryotic cells by regulating the expression of SLC7A11 (237). Therefore, the Nrf2 inhibitor triptolide disrupts GSH synthesis in tumor cells and is synthetically lethal in malignant tumors with IDH1 mutations (237). Many studies of inhibitors targeting system x_c ⁻ combined with other therapeutic approaches are also currently underway. Clinical trials of an FDA-approved xCT inhibitor, sulfasalazine (SAS), have been conducted in patients with recurrent glioblastoma. However, a recent study on melanoma indicated that xCT inhibition by SAS allows tumor cells to secrete PD-L1 via exosomes, inducing the M2 polarization of macrophages and leading to the development of resistance to anti-PD-1/PD-L1 therapy (238). Therefore, more detailed studies on the effects of SLC7A11 inhibitors as combination drugs in antitumor immunotherapy are required.

ASCT2-mediated glutamine uptake is inseparable from tumor cell growth and metabolism. GPNA was initially recognized as a commercially available competitive inhibitor of ASCT2, and has since been used in many cancer model studies. However, GPNA is not highly selective for ASCT2 and previous studies have shown that LAT1 and LAT2 are also inhibited by GPNA (239). V-9302 is considered an efficient ASCT2 competitive antagonist with significant inhibitory effects on tumor cell growth and proliferation, both in vivo and in vitro, while also inducing tumor cell death and oxidative stress (240). Nonetheless, follow-up studies have found that V-9302 has the same inhibitory function on SNAT2 and LAT1 (241). Therefore, specific ASCT2 inhibitors need to be further developed. Recently, monoclonal antibody (mAb) therapies targeting ASCT2 have been preliminarily studied. Suzuki et al. isolated three specific anti-ASCT2 mAbs, KM4008, KM4012, and KM4018, from CHO cells expressing ASCT2, and these effectively inhibited colorectal tumor growth in vitro (242). Another humanized anti-ASCT2 mAb, KM8094, exerts antitumor effects in gastric cancer patient-derived xenograft models, indicating its potential application in gastric cancer treatment (243).

L-type amino acid transporters are responsible for the uptake of the large neutral amino acids required for cell growth. By evaluating the antitumor effects of multiple anti-LAT1 mAbs, one study demonstrated that a novel anti-LAT1 mAb effectively inhibited tumor development and thus, it holds promise for cancer therapy (244). The small-molecule LAT1 inhibitor, JPH203, inhibits the growth of multiple solid tumors. Current phase I clinical trials of JPH203 suggest promising applications for the treatment of advanced biliary tract cancer (245).

Immune checkpoint blockade therapy can also be an effective cancer treatment by affecting transporter functions. For instance, immune checkpoint factors PD-1 and CTLA4 trigger immunosuppressive signaling pathways to inhibit the expression of the glucose transporter, GLUT1, and the glutamine transporters, SNAT1 and SNAT2, in T cells, thus limiting nutrient uptake and T cell activation, indicating that mAb drugs targeting immune checkpoints can restore T cell function (246).

Currently, there is limited published information regarding nucleoside transporter inhibitors. As a selective ENT inhibitor, NBMPR has been widely used in physiological and pharmacological studies of ENT function (247). The FDA-approved antiplatelet drug, ticagrelor, can inhibit ENT1 activity in human erythrocytes and platelets (248, 249). Rapamycin, another potent ENT1 inhibitor, interacts with FKBP to exert its biological function. The efficacy of rapamycin therapy at affecting cellular adenosine uptake and subsequent adenosine signaling suggests a potential new therapeutic strategy for regulating cellular adenosine signaling (250). The fused-pyrimidine nucleoside analog, thienopyrimidine 2′-deoxynucleoside (dMeThPmR) and its ribonucleoside analog (MeThPmR) are inhibitors with high affinity for hCNT1 (251). In colorectal cancer, the histone deacetylase inhibitor trichostatin A (TSA) effectively reverses the downregulation of CNT2 expression mediated by histone deacetylation and enhances the sensitivity of colorectal cancer cells to the chemotherapeutic drug cladribine (196).