Recent research suggests that certain MSS tumors may acquire MSI‐like features through EGFR/BRAF inhibition.[52] In this study, we propose a novel combination therapy using PRMT5i and CPT‐11, which enhances anti‐tumor immunity by leveraging epigenetic modifications that mediate PMS2 deficiency in MSS CRC. This evidence concerns the gene PMS2 and Marinesco-Sjogren syndrome.