Abstract

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.

Document Type

Article

Publication Date

2-2025

Notes/Citation Information

© 2025 The Author(s). Published by Elsevier Inc. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

Digital Object Identifier (DOI)

https://doi.org/10.1016/j.celrep.2025.115301

Funding Information

We would like to thank the following University of Utah Core Facilities: the HCI-High-Throughput Genomics and Bioinformatics Resources for performing scRNA-seq, the HSC Flow Cytometry Core Facility for cell sorting, and the DNA/Peptide Synthesis Core for primer synthesis. W.W.T. was funded by NIH grant 5F30CA260977, and R.M.O. was funded by NIH grant 5R01AG079477.

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