Abstract Metabolic rewiring, a defining hallmark of cancer, sustains cell proliferation and biosynthesis while coordinating adaptive interactions within the tumor microenvironment (TME). Recent advances reveal that metabolism in the TME-comprising stromal, immune and endothelial components forms a complex metabolic network in which intercellular competition, cooperation and plasticity profoundly influence tumor progression and therapeutic responses. Here we integrate emerging evidence on the organizational principles of amino acid and lipid metabolism within the TME, emphasizing how nutrient fluxes shape immune evasion, therapeutic resistance and metabolic symbiosis. We highlight key mechanisms through which cancer and nonmalignant cells engage in reciprocal nutrient manipulation, focusing on glutamine, arginine, tryptophan, branched-chain amino acids and lipids. The dual roles of these metabolites in immune regulation and tumor growth reveal the limitations of traditional single-pathway targeting and advocate for a network-centric therapeutic approach. We further discuss how metabolite-derived signaling and epigenetic regulation reinforce cell state transitions and immune suppression. Current and emerging therapeutic strategies, including multitarget combinations and immune–metabolic synergies, are evaluated alongside translational challenges. Finally, we underscore the need for spatial metabolomics, liquid biopsy platforms and artificial intelligence-driven modeling to map nutrient competition and cooperative exchange within the TME, offering new opportunities for precision metabolic interventions.
Sung et al. (Fri,) studied this question.