Tumor Microenvironment Cancer Immunotherapy Chronic Inflammation
Immunometabolism examines how metabolic pathways in the tumor microenvironment regulate antitumor immunity, immune escape, and therapeutic response. Rapid tumor growth alters nutrient availability and reprograms immune-cell metabolic pathways. Nutrient competition mainly involves glucose, glutamine, lipid, and amino acid metabolism, and it constrains T cells, NK cells, macrophages, and dendritic cells. Tumor cells, immune cells, and stromal cells create metabolic heterogeneity, where nutrient deprivation, lactate accumulation, hypoxia, and acidosis promote immune suppression[1][2][3][4].
Mechanistically, tumor cells gain proliferative advantages through increased glucose uptake, glycolysis, glutamine metabolism, and lipid metabolism, reducing available substrates for effector immune cells. Activated cytotoxic T cells and NK cells require glucose and amino acids, and nutrient restriction limits their proliferation and effector functions. Metabolites such as lactate, kynurenine, and adenosine create immunosuppressive signaling; IDO, CD73, arginase, lactate dehydrogenase, and amino acid transporters SLC1A5, SLC7A5, and SLC3A2 represent actionable experimental targets. SLC1A5 and SLC7A5 mediate glutamine and leucine uptake and participate in mTORC1- and c-Myc-linked metabolic regulation[2][4][5][6].
Disease applications center on cancer immunotherapy, immune checkpoint inhibitor resistance, CAR-T/CAR-NK metabolic fitness, malignant brain tumors, and solid-tumor metabolic targeting. Targeting glucose or glutamine metabolism with PD-1/PD-L1 blockade has a clear mechanistic rationale, and tumor metabolism-rewriting nanomedicines aim to regulate glucose, amino acid, lipid, and nucleotide metabolism to strengthen antitumor immunity. Current gaps include tumor metabolic plasticity, systemic toxicity, limited cell-type specificity, spatial metabolic gradients, and insufficient clinical biomarkers. Future experiments should integrate single-cell omics, spatial metabolomics, immune phenotyping, and metabolic inhibitor combinations to separate tumor-cell suppression from immune-cell preservation[1][3][5][7][8].
