CMTM6 is a transmembrane protein that functions as a master regulator of PD-L1 protein stability and surface expression 1. The protein localizes to plasma membrane and recycling endosomes, where it directly binds to PD-L1 and prevents its lysosomal degradation by blocking ubiquitination 12. CMTM6 maintains PD-L1 protein levels without affecting transcription, thereby extending PD-L1 half-life and enabling tumor immune evasion 2. Beyond PD-L1, CMTM6 also regulates CD58 expression, a costimulatory ligand important for T-cell activation, demonstrating its broader role in immune checkpoint regulation 3. The protein exhibits specificity for these immune regulators without affecting MHC class I expression 1. In cancer contexts, CMTM6 contributes to therapeutic resistance mechanisms - its overexpression correlates with trastuzumab resistance in HER2+ breast cancer through HER2 protein stabilization 4, and drives gemcitabine resistance in pancreatic cancer via an EP300-IGF2BP1 feedback loop 5. CMTM6 depletion enhances tumor-specific T-cell activity and alleviates immunosuppression 1, making it an attractive immunotherapy target. Its function can be antagonized by Hsc70, which competes for PD-L1 binding and promotes lysosomal degradation 6.