Immune checkpoint blockade (ICB) has greatly improved survival for mismatch repair-deficient metastatic colorectal cancer (dMMR/dCRC) patients, yet 40%–60% either fail to respond or develop acquired resistance (AR). This study established an anti-PD-1-resistant dCRC model and identified cytokine receptor-like factor 1 (CRLF1) as a key mediator of AR, whose upregulation impairs CD8+ T-cell anti-tumor immunity.