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<p>Immune checkpoint therapy (ICT) can induce durable tumor control but is limited by primary and acquired resistance. The mechanisms underlying immune-resistant tumor microenvironments (TMEs) remain incompletely understood. Here we show that deletion of microRNA-25 (miR-25) sensitizes tumors to ICT across multiple syngeneic mouse models. Single-cell transcriptomics reveals that miR-25 deficiency activates innate and humoral immunity by increasing major histocompatibility complex class II (MHC II) expression in tumor-associated macrophages (TAMs) and enhancing classical complement signaling in cancer-associated fibroblasts (CAFs). Complement activation shifts CAFs toward an inflammatory (iCAF) state, reduces suppressive crosstalk with TAMs, and promotes a pro-inflammatory TME. Mechanistically, miR-25 represses Syndecan-3 (SDC3) in response to interferon-γ (IFN-γ). Editing the miR-25 binding site in <i>Sdc3</i> restores SDC3 expression and overcomes resistance. These findings identify miR-25–mediated SDC3 repression as a driver of immune resistance and suggest strategies to convert immune-cold tumors into ICT-responsive hot tumors, offering avenues to enhance ICT.</p>

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microRNA-25 drives immune checkpoint therapy resistance by repressing innate and humoral immunity via Syndecan-3

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年5月20日

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  • Zhouting Zhu,
  • Wenyan Han,
  • Yufei Deng,
  • Zhaoyang Jia,
  • Gulshanbir Baidwan,
  • Lujing Wu,
  • Shweta Jakhmola,
  • Tongyun Wang,
  • Dhenugen Logeswaran,
  • Jing Wen,
  • Amanda Y. Sun,
  • Bill Bray,
  • Na Li,
  • Lingling Wang,
  • Hui Hui,
  • Jiaqian Wu,
  • Sandip Pravin Patel,
  • Tariq M. Rana

摘要

Immune checkpoint therapy (ICT) can induce durable tumor control but is limited by primary and acquired resistance. The mechanisms underlying immune-resistant tumor microenvironments (TMEs) remain incompletely understood. Here we show that deletion of microRNA-25 (miR-25) sensitizes tumors to ICT across multiple syngeneic mouse models. Single-cell transcriptomics reveals that miR-25 deficiency activates innate and humoral immunity by increasing major histocompatibility complex class II (MHC II) expression in tumor-associated macrophages (TAMs) and enhancing classical complement signaling in cancer-associated fibroblasts (CAFs). Complement activation shifts CAFs toward an inflammatory (iCAF) state, reduces suppressive crosstalk with TAMs, and promotes a pro-inflammatory TME. Mechanistically, miR-25 represses Syndecan-3 (SDC3) in response to interferon-γ (IFN-γ). Editing the miR-25 binding site in Sdc3 restores SDC3 expression and overcomes resistance. These findings identify miR-25–mediated SDC3 repression as a driver of immune resistance and suggest strategies to convert immune-cold tumors into ICT-responsive hot tumors, offering avenues to enhance ICT.