What question did this study set out to answer?

This study aims to investigate the role of microRNA-25 in resistance to immune checkpoint therapy by exploring its effects on innate and humoral immunity.

May 22, 2026Open Access

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

Key Points

This study aims to investigate the role of microRNA-25 in resistance to immune checkpoint therapy by exploring its effects on innate and humoral immunity.
Used syngeneic mouse models to examine the effects of miR-25 deletion on tumor sensitivity to immune checkpoint therapy.
Conducted single-cell transcriptomics to analyze changes in immune characteristics and signaling pathways in the tumor microenvironment.
Manipulated the miR-25 binding site in Syndecan-3 to restore its expression and assess therapeutic outcomes.
miR-25 deletion sensitizes tumors to immune checkpoint therapy across multiple models, enhancing treatment efficacy.
Increased MHC II expression in tumor-associated macrophages and enhanced complement signaling in cancer-associated fibroblasts were observed after miR-25 deletion.
Editing the miR-25 binding site restored SDC3 expression and overcame resistance to immune checkpoint therapy.

Abstract

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.

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