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However, a portion of MSI\u2010H CRC patients still experience adverse disease outcomes. We aimed to identify the tumor\u2010autonomous regulators determining these heterogeneous clinical outcomes. The Cancer Genome Atlas (TCGA) dataset was used to identify regulators in MSI\u2010H CRC patients with unfavorable outcomes. Stable CRC tumor clones expressing targeted regulators were established to evaluate migratory and stemness properties, immune cell vulnerability, and cell\u2010in\u2010cell (CIC) structure formation. RNA\u2010sequencing (RNA\u2010seq) was used to identify enriched biological pathways in stable CRC tumor clones. Clinicopathological characterization of formalin\u2010fixed paraffin\u2010embedded (FFPE) MSI\u2010H CRC specimens was performed to explore the underlying mechanisms involved. We showed that cancer\/testis antigen family 45 member A1 (\n                    <jats:italic>CT45A1<\/jats:italic>\n                    ) expression was upregulated in MSI\u2010H CRC patients with poor survival outcomes. CT45A1\u2010expressing microsatellite stable (MSS) CRC cells showed enhanced migratory ability. However, CT45A1\u2010expressing MSI\u2010H CRC cells, but not MSS CRC cells, showed higher resistance to natural killer (NK) cell cytotoxicity and served as outer cells in homotypic CIC structures, preventing exogenous or therapeutic antibody access to inner CRC\u00a0cells. Inactivating RHO\u2010ROCK\/MLCK\u2010MLC2 signaling with small\u2010molecule inhibitors or short\u2010hairpin RNAs (shRNAs) targeting myosin light chain kinase (\n                    <jats:italic>MYLK<\/jats:italic>\n                    ) abolished NK cell resistance and reduced the outer cell fate of CT45A1\u2010expressing MSI\u2010H CRC cells. In MSI\u2010H CRC patients, CT45A1\u2010positive tumors exhibited increased MLC2 phosphorylation, increased outer cell fate, and decreased survival. We demonstrated that CT45A1 potentiates the advanced progression of MSI\u2010H CRC, and targeting MLC2 phosphorylation may enhance immunotherapy efficacy in CT45A1\u2010positive MSI\u2010H CRC patients.\n                  <\/jats:p>","DOI":"10.1002\/1878-0261.13736","type":"journal-article","created":{"date-parts":[[2024,9,26]],"date-time":"2024-09-26T00:18:58Z","timestamp":1727309938000},"page":"430-451","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["<scp>CT45A1<\/scp>\n                    \u2010mediated\n                    <scp>MLC2<\/scp>\n                    (\n                    <scp>MYL9<\/scp>\n                    ) phosphorylation promotes natural killer cell resistance and outer cell fate in a cell\u2010in\u2010cell structure, potentiating the progression of microsatellite instability\u2010high colorectal 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