MicroRNAs in Colorectal Cancer Immunotherapy: Biomarkers, Resistance Mechanisms, and Strategies to Convert “Cold” Tumors to “Hot”

Abstract

Colorectal cancer (CRC) remains a major cause of cancer morbidity and mortality. Immune checkpoint inhibitors (ICIs) have transformed the treatment of microsatellite instability-high/mismatch repair-deficient (MSI-H/dMMR) CRC, yet most CRCs are microsatellite-stable/mismatch repair-proficient (MSS/pMMR) and remain poorly responsive to immunotherapy. MicroRNAs (miRNAs) are well positioned to influence this biology because individual miRNAs can coordinate multiple tumor-intrinsic and microenvironmental programs that shape antitumor immunity. Rather than cataloging miRNAs one by one, this review organizes the evidence around the major barriers that sustain an immune-cold CRC microenvironment: altered checkpoint and costimulatory signaling, defective antigen presentation, impaired effector T-cell access and function, suppressive myeloid and stromal compartments, and extracellular vesicle (EV)-mediated intercellular communication. We also critically assess tissue and circulating miRNA signatures as candidate biomarkers of ICI response and discuss therapeutic approaches based on miRNA mimics, inhibitors, and targeted delivery platforms. The available evidence supports a biologically compelling role for miRNA networks in CRC immune regulation, but clinical translation remains limited by context dependence, delivery, off-target effects, and the lack of treatment-linked validation in CRC cohorts.