MS4A12 is a colon-specific membrane-spanning four-transmembrane protein 1 that functions as a store-operated calcium (Ca2+) channel involved in cell differentiation and proliferation. MS4A12 exhibits store-operated Ca2+ entry (SOCE) activity uniquely in colonic tissues 2 and contributes to SOCE through complex formation with Orai1, independent of STIM1 cooperation 2. The gene is transcriptionally regulated by the CDX2 homeobox transcription factor, which binds to a single element in the MS4A12 promoter, ensuring colon-specific expression 3. Mechanistically, MS4A12 sensitizes cells for epidermal growth factor-mediated proliferation and chemotaxis 3, and its expression is critical for normal colonic epithelial differentiation 4. In colorectal cancer, MS4A12 expression is dramatically decreased with cancer progression 2. Clinically, MS4A12 serves as a significant diagnostic and prognostic biomarker; low MS4A12 expression predicts worse overall survival in early-stage colorectal cancer 4 and is identified among hub genes distinguishing primary colorectal cancer from normal tissue 5. Additionally, MS4A12 genetic variants (rs4939378) predict response to oxaliplatin-based chemotherapy in stage III and metastatic colorectal cancer 67, with potential utility as pharmacogenetic markers for treatment selection.