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Colorectal cancer (CRC) remains a major global health burden, and despite advances in systemic therapy, outcomes for metastatic disease remain poor. A central challenge in CRC immuno-oncology is the limited applicability of immune checkpoint blockade (ICB): only a small subset of patients—those with mismatch repair deficiency (dMMR)—derive substantial benefit, leaving the majority of patients with microsatellite stable (MSS) disease without effective immunotherapeutic options.1 2 This unmet need has driven intensive efforts to identify additional biomarkers that can better stratify patients and guide immunotherapy strategies.