Stromal Metabolism Found to Dominate Immune Suppression in Tumor Microenvironment
A review highlights that stromal cell metabolism in the tumor microenvironment dominates immune suppression. Cancer-associated fibroblasts and adipocytes release metabolites that impair antitumor immunity while favoring tumor-promoting immune cells. Targeting these metabolic networks could restore immune function and boost immunotherapy efficacy.
The metabolism of nonmalignant stromal cells within the tumor microenvironment, particularly cancer-associated fibroblasts and adipocytes, is a dominant force sculpting immune responses and driving therapeutic resistance, according to a recent review. The findings highlight how these metabolically active hubs release and redistribute key metabolites such as lactate, fatty acids, and amino acids to modulate both tumor cells and infiltrating immune cells.
The tumor microenvironment is a complex ecosystem in which malignant cells coexist with diverse stromal and immune populations. While tumor-intrinsic metabolic programs have been extensively studied, emerging evidence now points to stromal metabolism as the primary orchestrator of intercellular communication. Cancer-associated fibroblasts often adopt a glycolytic phenotype, producing large amounts of lactate that suppress cytotoxic immune activity and promote angiogenesis. They also reprogram glucose, amino acid, and lipid metabolism, and secrete paracrine mediators that stimulate tumor proliferation and immune escape.
Cancer-associated adipocytes, historically recognized for lipid storage, undergo dedifferentiation-like changes upon receiving tumor-derived signals. They lose their lipid storage capacity and instead release cytokines, adipokines, and fatty acids that rewire immune cell metabolism and foster a tumor-permissive niche supportive of cancer growth and metastasis.
These metabolic exchanges create a nutrient-restricted and immunosuppressive environment that varies in its effects on different immune subsets. Cytotoxic CD8+ T lymphocytes and natural killer cells exhibit reduced proliferation, cytokine production, and cytolytic capacity, while tumor-promoting populations such as M2-polarized macrophages and regulatory T cells gain a metabolic advantage. The review further identifies mechanisms including nutrient competition, mitochondrial remodeling, redox imbalance, and immunometabolic rewiring as key drivers of this immunosuppressive state.
Deciphering these multilayered metabolic interactions, the study notes, could establish a foundation for reprogramming the tumor microenvironment, restoring immune competence, and enhancing the efficacy of current immunotherapies through metabolism-targeted interventions.