Lipid oxidation reprogramming in cancer-associated fibroblasts enhances CD8+ T cell cytotoxicity and therapeutic response

Cancer-associated fibroblasts (CAFs) are major stromal components of the tumor microenvironment, yet how their metabolic states shift during therapy and influence anti-tumor immunity remains unclear. By integrating clinical cancer samples, single-cell RNA analyses, and functional studies, we identify a chemotherapy-conditioned PTGER3 + CAF subset characterized by enhanced lipid oxidation. This metabolic reprogramming strengthens antitumor immunity by promoting CD8 + T cell activation and cytotoxicity through the suppression of PTEN-related signaling. Clinically, higher proportions of therapy-induced PTGER3 + CAFs correlate with improved treatment responses and better patient prognosis. Together, these findings reveal a previously unrecognized stromal metabolic adaptation that supports CD8 + T cell immunity and highlight CAF-driven lipid oxidation and its regulation of CD8 + T cell PTEN signaling as potential avenues to enhance chemotherapy and immunotherapy efficacy.