The rising incidence of advanced-stage colorectal cancer (CRC) and poor survival outcomes necessitate new and effective therapies. Immune checkpoint inhibitors (ICIs), specifically anti-PD-1 therapy, show promise, yet clinical determinants of a positive response are suboptimal. Here, we identify microRNA-155 (miR-155) as necessary for CD8 T cell-infiltrated tumors through an unbiased in vivo CRISPR-Cas9 screen identifying functional tumor antigen-specific CD8 T cell-expressed microRNAs. T cell miR-155 is required for anti-PD-1 responses and for a vital intratumor CD8 T cell differentiation cascade by repressing Ship-1, inhibiting Tcf-1 and stemness, and subsequently enhancing Cxcr6 expression, anti-tumor immunity, and effector functions. Based on an underlying miR-155-dependent CD8 T cell transcriptional profile, we identify a gene signature that predicts ICI responses across 12 diverse cancers. Together, our findings support a model whereby miR-155 serves as a central regulator of CD8 T cell-dependent cancer immunity and ICI responses that may be leveraged for future therapeutics.
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| http://dx.doi.org/10.1016/j.celrep.2025.115301 | DOI Listing |
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