CT45A1, a vital driver of the RHO‐ROCK/MLCK‐MLC2 signaling, is found to enhance cancer cell resistance to natural killer (NK) cell killing and generate a protective cell‐in‐cell (CIC) structure in microsatellite instability‐high (MSI‐H) colorectal cancer (CRC) cells. Here, CT45A1 is linked to cancer.