Decoding the metabolic dialogue in the tumor microenvironment: from immune suppression to precision cancer therapies

Abstract

The tumor microenvironment (TME) represents a metabolic battleground where immune cells and cancer cells vie for essential nutrients, ultimately influencing antitumor immunity and treatment outcomes. Recent advancements have shed light on how the metabolic reprogramming of immune cells, including macrophages, T cells, and DCs, determines their functional polarization, survival, and interactions within the TME. Factors such as hypoxia, acidosis, and nutrient deprivation drive immune cells toward immunosuppressive phenotypes, while metabolic interactions between tumors and stromal cells further entrench therapeutic resistance. This review synthesizes new insights into the metabolic checkpoints that regulate immune cell behavior, focusing on processes like glycolysis, oxidative phosphorylation (OXPHOS), lipid oxidation, and amino acid dependencies. We emphasize how metabolic enzymes (e.g., IDO1, ACLY, CPT1A) and metabolites (e.g., lactate, kynurenine) facilitate immune evasion, and we propose strategies to reverse these pathways. Innovations such as single-cell metabolomics, spatial profiling, and AI-driven drug discovery are transforming our understanding of metabolic heterogeneity and its clinical implications. Furthermore, we discuss cutting-edge therapeutic approaches-from dual-targeting metabolic inhibitors to biomaterial-based delivery systems-that aim to reprogram immune cell metabolism and enhance the effectiveness of immunotherapy. Despite the promise in preclinical studies, challenges persist in translating these findings to clinical applications, including biomarker validation, metabolic plasticity, and interpatient variability. By connecting mechanistic discoveries with translational applications, this review highlights the potential of immunometabolic targeting to overcome resistance and redefine precision oncology.

Keywords: Immune cells metabolism; Immunotherapy resistance; Metabolic reprogramming; Therapeutic targeting; Tumor microenvironment.

Fig. 1

The metabolism-related mechanisms of immune cells in tumors and the existing treatment strategies targeting immune cell metabolism. Created with BioRender.com

Fig. 2

A timeline for the development of tumor immunology and the TME. The upper section primarily discusses recent developments in cancer research, whereas the lower section highlights advancements in metabolism. Created with BioRender.com

Fig. 3

The main metabolism of tumor cells promotes their growth. Cells and their three most essential metabolic pathways—glucose metabolism, lipid metabolism, and amino acid metabolism—play a crucial role in cellular function. Among these pathways, the Warburg effect stands out as a hallmark of tumor glucose metabolism. The mechanisms discussed in the article are illustrated on the left side of the figure, along with recent related studies. In tumor cells, amino acid metabolism largely centers around glutamine, which is primarily regulated by transporter proteins. Additionally, lipid metabolism in tumor cells encompasses pathways associated with cholesterol and fatty acids, which are vital for supporting tumor growth and metastasis. Created with BioRender.com. DHHC9 Asp—His—His—Cys box—containing protein, 9FOXM1—PROTAC Forkhead box M1—Proteolysis—Targeting Chimera, p53 Tumor protein p53, GLUT1 Glucose Transporter 1, Cd Cadmium, SLC1A5 Solute Carrier Family 1 Member 5, SLC7A11 Solute Carrier Family 7 Member 11, SUCLA2 Succinate—CoA Ligase, GOT2 Glutamic—Oxaloacetic Transaminase 2, CD36 CD36 Molecule, 27HC 27—Hydroxycholesterol; PPAR Peroxisome Proliferator—Activated Receptor, HDAC—1/2 Histone Deacetylase ½, SREBP-1 Sterol Regulatory Element Binding Protein 1, NPC2 Niemann—Pick Disease Type C2 Protein, METTL5 Methyltransferase Like 5, SIRT1 Sirtuin 1

Fig. 4

The anti-tumor and pro-tumor metabolic functions of four types of innate immune cells: macrophages, neutrophils, dendritic cells, and NK cells. In macrophages, anti-tumor effects are linked to energy supply, inhibitory metabolic products, and immunoregulatory factors, whereas pro-tumor functions are associated with supporting immunosuppressive phenotypes and the production of various factors. For neutrophils, anti-tumor activity is connected to energy metabolism, metabolic toxicity, and the generation of reactive oxygen species (ROS). Conversely, their pro-tumor roles involve the suppression of T cells, the promotion of the Warburg effect, and support for immunosuppressive neutrophils. Dendritic cells exhibit anti-tumor responses through the metabolic activation of cytokine secretion and GPR81-mediated tumor control; however, their pro-tumor effects arise from nutrient competition, ROS production, and lipid accumulation. Lastly, NK cells demonstrate anti-tumor functions through enhanced cytotoxicity and cytokine production, while their pro-tumor effects stem from nutrient deprivation and metabolic inhibition. Created with BioRender.com. ROS Reactive Oxygen Species, PPP Pentose Phosphate Pathway, NO Nitric Oxide, Gln Glutamine, Arg1 Arginase 1, DC Dendritic Cell, NK Natural Killer Cell, FAO Fatty Acid Oxidation

Fig. 5

The three primary metabolic pathways of T cells and their contributions to anti-tumor and pro-tumor effects. Normal glucose metabolism is strongly linked to T cell-mediated anti-tumor activity. However, metabolic feedback, particularly concerning pathways related to phosphoenolpyruvate (PEP), can restrict glucose availability. Additionally, tumor cells within the tumor microenvironment (TME) compete with T cells for glucose, while the accumulation of reactive oxygen species (ROS) further facilitates tumor metastasis. In terms of amino acid metabolism, the mTOR pathway plays a crucial role in regulating T cell renewal and maintaining their anti-tumor functions. For lipid metabolism, fatty acid metabolism is essential for the activation of anti-tumor T cells, cholesterol metabolism meets the requirements for T cell proliferation, and phospholipid metabolism enhances T regulatory cell (Treg) function, potentially inhibiting overall T cell proliferation. Created with BioRender.com; Th1 cell T—helper 1 cell, Th17 cell T—helper 17 cell, FAS Fatty Acid Synthase, CD8 + cell Cluster of Differentiation 8—positive cell, PTEN Phosphatase and Tensin Homolog, PIP2 Phosphatidylinositol 4,5—bisphosphate, PIP3 Phosphatidylinositol 3,4,5—trisphosphate, DAG Diacylglycerol, PKC Protein Kinase C, NFAT Nuclear Factor of Activated T—cells; NF—κB Nuclear Factor—kappa B, Leu Leucine, Arg Arginine, Met Methionine

Fig. 6

The metabolic processes of Tregs and MDSCs and their mechanisms in promoting immune escape. Lactate metabolism primarily promotes Treg function through the Krebs cycle, whereas amino acids exert their effects via the mTOR pathway. In MDSCs, it is noteworthy that tumor-derived factors such as IL-6 and G-CSF can also enhance MDSC proliferation. Created with BioRender.com

Fig. 7

Mechanisms of Immunometabolic Therapy. Metabolism-focused cancer therapies aim to inhibit tumor growth by targeting specific metabolic pathways. Key metabolic agents in chemotherapy include metformin, DCA, and CB-839. Metformin activates the AMPK pathway, while DCA enhances the activity of the pyruvate dehydrogenase complex, thereby suppressing tumor glycolysis. CB-839 inhibits glutaminase (GLS), leading to an accumulation of glutamate and metabolic disruption within tumor cells. These metabolism-targeted therapies act on crucial metabolic enzymes such as hexokinase 2 (HK2), fatty acid synthase (FASN), ATP synthase, and isocitrate dehydrogenase (IDH), thus impeding tumor progression. Furthermore, metabolism-based immunotherapy enhances T cell function by improving T cell metabolism, remodeling energy supply, and delaying T cell exhaustion. Additionally, metabolism-related biomaterials—such as nab-PTX, AGuIX, and photothermal therapy (PTT)—deliver anti-tumor effects through mechanisms such as drug delivery, photothermal therapy, and the generation of reactive oxygen species (ROS). Created with BioRender.com. OCTs Organic Cation Transporters, DCA Dichloroacetate; AMPK AMP—Activated Protein Kinase, mTORC1 Mammalian Target of Rapamycin Complex 1, GAS Glutamic Acid Stacking, HK2 Hexokinase 2, 2—DG 2—Deoxyglucose, LFA Long—Chain Fatty Acid, IDH Isocitrate Dehydrogenase, PTX Paclitaxel, nab—PTX Nanoparticle—Albumin—Bound Paclitaxel, AuNPs Gold Nanoparticles