CMTM4 (CKLF like MARVEL transmembrane domain containing 4) is a type-3 transmembrane protein that serves as a critical regulator of immune checkpoint signaling and tumor immunity. CMTM4 acts as a backup regulator for CMTM6 in maintaining PD-L1 protein stability at the plasma membrane 1. The protein directly associates with PD-L1, reducing its ubiquitination and increasing protein half-life without affecting transcription levels, thereby enhancing tumor cells' ability to inhibit T-cell responses 1. Energy deprivation can disrupt CMTM4-PD-L1 interactions through AMPK-mediated phosphorylation of PD-L1 at Ser283, leading to PD-L1 degradation 2. Beyond PD-L1 regulation, CMTM4 promotes tumor progression through multiple mechanisms. It enhances EGFR signaling by promoting receptor recycling and preventing degradation, while activating NF-κB, mTOR, and PI3K/Akt pathways 3. CMTM4 creates an immunosuppressive tumor microenvironment by promoting myeloid-derived suppressor cell expansion through CCL2/CCR2 and IL-6/GP130 signaling axes 4. Additionally, exosomal CMTM4 induces M2 macrophage polarization and enhances immunosuppressive cytokine secretion 5. Clinically, CMTM4 inhibition sensitizes tumors to EGFR inhibitors, chemotherapy, and anti-PD-1 immunotherapy, making it a promising therapeutic target 345.