转录因子介导的癌相关成纤维细胞重编程揭示实体瘤的可靶向脆弱性

Cancer-associated fibroblasts (CAFs) contribute to immune exclusion and therapy resistance in solid tumors, limiting the efficacy of chimeric antigen receptor (CAR) T cell and immune cell therapy. To overcome this, we developed a transcription factor (TF)-based strategy to reprogram prostate-derived CAFs (pCAFs) into normal fibroblast-like cells (NFs).

We prioritized TFs enriched in quiescent stellate cells-Vitamin D receptor (VDR), Peroxisome Proliferator-Activated Receptor gamma (PPAR ), and p53-and selected VDR for proof-of-concept studies. Lentiviral VDR expression in pCAFs produced VDR-reprogrammed NFs (VDR-rpNFs) with reduced CAF markers, increased ATP, and suppressed TGF- and IL6, indicating phenotypic and metabolic reversion.

In both in vitro 3D co-cultures and in vivo , VDR-rpNFs disrupted tumor architecture, enhanced CAR T cell infiltration, and reduced necrosis. PPAR - and p53-rpNFs showed similar reprogramming effects. These results suggest TF-guided fibroblast reprogramming as a viable strategy to remodel the tumor microenvironment and improve CAR T cell efficacy in solid tumors.