Metabolic Reprogramming of Cancer-Associated Fibroblasts Orchestrates the Immunosuppressive Microenvironment in Breast Cancer

College of Clinical Medicine, Hebei University of Engineering, 056038, Handan, Hebei, China

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Abstract

The involvement of cancer-associated fibroblasts in the breast cancer microenvironment is pivotal in immunosuppression by metabolic reprogramming. This research will seek to do a systematic dissection of how CAF metabolic reprogramming initiates two separate pathways mediated by metabolites and exosomes responsible for tumor immune escape, and suggest that these mechanisms might be countered by targeting of major metabolic enzymes or modulating exosome-derived non-coding RNAs as new ways to reverse immunosuppression and improve immunotherapy workability in breast cancer. Specifically, CAFs exhibit an inverse Warburg effect with high glycolysis, producing excess lactate exported via MCT4 into the TME, acidifying it to pH 6.0-6.5. This inhibits T cell cytotoxicity and polarizes macrophages toward the M2 lineage. Simultaneously, CAFs activate glutamine synthetase for increased glutamine production, supporting tumor-associated macrophages’ pro-tumorigenic activities. Additionally, CAF-derived exosomes transport metabolic enzymes, miRNAs, and mRNAs, transmitting inhibitory signals to enhance immunosuppression. Overall, these facts indicate that CAF metabolic reprogramming is at the center of immunosuppressive tumor microenvironment remodeling and can serve as actionable targets of combinatorial immunotherapy.