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bioRxiv · 10.64898/2026.04.15.718753

Transcription Factor-Mediated Reprogramming of Cancer-Associated Fibroblasts Reveals Targetable Vulnerabilities in Solid Tumors

Lee, N. S.·Datta, P.·Huang, Y.·Raykowski, B.·Yu, X.·Guo, T.·He, P.·Moolayadukkam, S.·Xiong, S.·Yoon, C. W.·Wang, Y.·DeRenzo, C.·Pinski, J.·Puri, I. K.
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Abstract

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{gamma}), 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-{beta} 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{gamma}- 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.

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Lee, N. S., Datta, P., Huang, Y., Raykowski, B., Yu, X., Guo, T., He, P., Moolayadukkam, S., Xiong, S., Yoon, C. W., Wang, Y., DeRenzo, C., Pinski, J., Puri, I. K.. 2026-04-20. Transcription Factor-Mediated Reprogramming of Cancer-Associated Fibroblasts Reveals Targetable Vulnerabilities in Solid Tumors. https://doi.org/10.64898/2026.04.15.718753

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