Altogether, our study i) identified CMTM6 as a shared regulator and molecular partner of the CD58 and PD-L1 proteins, ii) revealed fundamental insight into CD58 regulation, iii) described CMTM6 as a modulator of immune responses through such regulations, and with a possible relevance of the CD58/CMTM6 interaction in human cancer lesions. Here, CD58 is linked to cancer.