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Updated: May 5, 2026

Cancer-Associated Fibroblasts from Mouse Mammary Tumors as Tools for Molecular and Computational Studies
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Cancer-Associated Fibroblasts from Mouse Mammary Tumors as Tools for Molecular and Computational Studies

Published on: July 3, 2025

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

Nan Sook Lee, Priyankan Datta, Yixuan Huang

    Biorxiv : the Preprint Server for Biology
    |May 4, 2026
    PubMed

    Insights

    Reprogramming cancer-associated fibroblasts (CAFs) into normal fibroblasts using transcription factors enhances chimeric antigen receptor (CAR) T cell therapy efficacy by improving T cell infiltration and reducing tumor resistance.

    Area of Science:

    • Oncology
    • Immunotherapy
    • Cell Biology

    Background:

    • Cancer-associated fibroblasts (CAFs) create an immunosuppressive tumor microenvironment, hindering effective cancer therapies like chimeric antigen receptor (CAR) T cell therapy.
    • CAFs contribute to immune exclusion and resistance to treatments in solid tumors.

    Purpose of the Study:

    • To develop a novel strategy for reprogramming CAFs into normal fibroblasts (NFs) to overcome tumor-induced immune suppression.
    • To investigate the potential of transcription factor (TF)-guided fibroblast reprogramming to enhance CAR T cell therapy.

    Main Methods:

    • Developed a TF-based reprogramming strategy using Vitamin D receptor (VDR), Peroxisome Proliferator-Activated Receptor gamma (PPARγ), and p53.
    • Utilized lentiviral expression to reprogram prostate-derived CAFs (pCAFs) into VDR-reprogrammed NFs (VDR-rpNFs).
    • Evaluated reprogramming efficacy through in vitro 3D co-cultures and in vivo models, assessing CAF markers, metabolic activity, cytokine production, tumor architecture, T cell infiltration, and necrosis.

    Main Results:

    • VDR-rpNFs exhibited reduced CAF markers and suppressed immunosuppressive factors (TGF-β, IL6), alongside increased metabolic activity (ATP).
    • Reprogrammed fibroblasts disrupted tumor architecture, significantly enhancing CAR T cell infiltration into tumors.
    • Both VDR-rpNFs and reprogrammed NFs using PPARγ and p53 demonstrated similar beneficial reprogramming effects.

    Conclusions:

    • Transcription factor-guided reprogramming is a promising approach to reverse CAF phenotype and remodel the tumor microenvironment.
    • This strategy holds potential for improving the efficacy of CAR T cell therapy and other immune cell therapies in solid tumors.
    • Targeting fibroblasts offers a new avenue to overcome therapeutic resistance driven by the tumor microenvironment.

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