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

Zhouting Zhu1,2, Wenyan Han1, Yufei Deng1

  • 1Department of Cellular and Molecular Medicine, University of California San Diego, 9500 Gilman Drive, La Jolla, California, USA.

Nature Communications
|May 20, 2026
PubMed

Insights

Deleting microRNA-25 (miR-25) enhances immune checkpoint therapy (ICT) effectiveness by reprogramming the tumor microenvironment. This approach converts immune-cold tumors into hot tumors responsive to ICT, improving cancer treatment outcomes.

Area of Science:

  • Immunology
  • Oncology
  • Molecular Biology

Background:

  • Immune checkpoint therapy (ICT) shows promise for durable tumor control but faces challenges with primary and acquired resistance.
  • The mechanisms driving immune-resistant tumor microenvironments (TMEs) are not fully understood, hindering broader therapeutic success.

Purpose of the Study:

  • To investigate the role of microRNA-25 (miR-25) in regulating TME and ICT resistance.
  • To identify novel strategies for overcoming resistance and enhancing ICT efficacy.

Main Methods:

  • Utilized syngeneic mouse models to study the effects of miR-25 deletion on ICT response.
  • Employed single-cell transcriptomics to analyze immune cell populations and signaling pathways within the TME.
  • Investigated the molecular mechanism of miR-25 action involving Syndecan-3 (SDC3) and interferon-gamma (IFN-γ).

Main Results:

  • miR-25 deletion sensitized tumors to ICT across multiple models.
  • Loss of miR-25 activated innate and humoral immunity by upregulating MHC II on TAMs and enhancing complement signaling in CAFs.
  • Complement activation promoted a pro-inflammatory TME by shifting CAFs to an iCAF state and reducing suppressive crosstalk with TAMs.
  • miR-25 was found to repress SDC3 in response to IFN-γ; restoring SDC3 expression overcame resistance.

Conclusions:

  • miR-25-mediated repression of SDC3 is a key mechanism driving immune resistance to ICT.
  • Targeting miR-25 or restoring SDC3 expression can convert immune-cold tumors into ICT-responsive hot tumors.
  • These findings offer potential therapeutic strategies to enhance ICT efficacy in cancer treatment.

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