Metabolic crosstalk among cancer-associated fibroblasts, adipocytes and immune cells as an immunosuppressive tumor microenvironment driver

Abstract

The tumor microenvironment (TME) is a complex ecosystem composed of not only malignant cells but also diverse stromal and immune cell populations that collectively shape tumor behavior. Metabolism is a central regulator of the TME, orchestrating intercellular communication through altered nutrients and signaling pathways to influence both the metabolic plasticity of cancer cells and functional balance of immune populations, ultimately determining tumor progression and antitumor immunity. Although tumor-intrinsic metabolic programs have been extensively characterized, emerging evidence highlights stromal metabolism as the dominant force sculpting immune responses within the TME. Among the nonmalignant stromal constituents, cancer-associated fibroblasts and cancer-associated adipocytes have emerged as metabolically active hubs that release and redistribute key metabolites, such as lactate, fatty acids and amino acids, to modulate the activity of both tumor and immune cells. Here we integrate recent advances in the understanding of stromal-immune metabolic crosstalk and elucidates how diverse metabolic mechanisms, including nutrient competition, mitochondrial remodeling, redox imbalance and immunometabolic rewiring, collectively reinforce an immunosuppressive TME and drive therapeutic resistance. Our study highlights the emerging strategies for selectively reprogramming these metabolic networks as potential therapeutic avenues. Deciphering these multilayered interactions will establish a conceptual and mechanistic foundation for reprogramming TME, restoring immune competence and enhancing the efficacy of current immunotherapies through metabolism-targeted interventions.