TMEM199 promotes PD-L1 expression and tumor immune evasion by activating the recycling of IFNGR1/2.

Immune checkpoint blockade (ICB) therapies targeting the programmed cell death 1 (PD-1)/PD-1 ligand 1 (PD-L1) axis provide significant clinical benefits across multiple tumor types. Although interferon (IFN)-γ is essential for anti-tumor immunity, sustained IFN-γ signaling in the tumor microenvironment potently upregulates PD-L1 expression in tumor cells and induces profound T cell exhaustion, limiting the efficacy of ICB therapies. Therefore, further investigation into the regulation of IFN-γ-PD-L1 signaling is necessary for the development of more effective therapeutic strategies. Herein, transmembrane protein 199 (TMEM199) is identified as a novel regulator of IFN-γ-driven PD-L1 transcription. Mechanistically, TMEM199 and its important partner coiled-coil domain containing 115 (CCDC115) interact with IFNGR1/2 and facilitate their trafficking to RAB11A-positive recycling endosomes. TMEM199/CCDC115 also recruits transport protein particle (TRAPP) Ⅱ to the recycling endosomes and activates RAB11A, leading to enhanced IFNGR1/2 recycling and downstream PD-L1 upregulation. Collectively, these findings reveal that TMEM199 might be a promising therapeutic target for immunotherapy.