We confirmed that, specifically in MSI‐H CRC cells, CT45A1 expression drives RHO‐ROCK/MLCK‐MLC2 signaling to enhance cancer cell resistance to NK cell cytotoxicity and generates a protective CIC structure, with CT45A1‐expressing cells becoming outer cells shielding the inner cancer cells from targeted antibody therapy and potentially subsequent antitumor immunity. Here, CT45A1 is linked to cancer.