microRNA-25 drives immune checkpoint therapy resistance by repressing innate and humoral immunity via Syndecan-3.
basic_science · Level V
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- Record sourced from PubMed, PMID 42161938.
- Also identified by DOI 10.1038/s41467-026-73339-y.
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Abstract
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.