Fasting-Mimicking Diets Reprogram Cancer-Associated Fibroblasts to Reverse the Immunosuppressive Tumor Microenvironment in Breast Cancer

Abstract Fasting-mimicking diets (FMD) have been reported to increase the antitumor efficacy in preclinical studies in various cancers. FMD can affect the tumor microenvironment (TME), and elucidating the mechanisms and cells mediating the effects of FMD may uncover combination treatment strategies. Here, we performed single-cell transcriptomic sequencing to characterize the TME changes induced by FMD intervention in a mouse model of spontaneous breast cancer. The sequencing data indicated that FMD suppressed tumor cell stemness, promoted apoptosis, and increased the infiltration of innate and adaptive immune cells, especially natural killer (NK) cells and effector CD8+ T cells. Importantly, FMD induced phenotypic reprogramming of cancer-associated fibroblasts (CAF), leading to a decrease in the immunosuppressive inflammatory CAF (iCAF) subset. Mechanistically, FMD decreased platelet-derived growth factor C (PDGFC) secretion in tumor cells by reducing glucose levels and inhibiting glycolysis to reprogram CAFs. PDGFC increased the activation of the JAK–STAT3 pathway, which induced iCAF differentiation. Combining FMD with PDGF receptor (PDGFR) inhibitors increased the efficacy of anti–PD-L1 immunotherapy in vivo. Overall, this study reveals a mechanism of metabolic–immune rewiring through which FMD suppresses tumor progression, providing preliminary evidence for the potential of combination FMD-based strategies in breast cancer treatment. Significance: Fasting-mimicking diet blocks breast cancer cell-induced generation of immunosuppressive fibroblasts, thereby facilitating tumor infiltration of immune cell and stimulating antitumor immunity to sensitize breast cancer to immunotherapy.