DRG2 is required for surface localization of PD-L1 and the efficacy of anti-PD-1 therapy
More than half of patients with tumors that have high PD-L1 expression do not respond to anti-PD-1/PD-L1 therapy, and the reasons for this remain unclear. In this study, we demonstrate that developmentally regulated GTP-binding protein 2 (DRG2) is essential for the response of PD-L1-expressing tumors to anti-PD-1 treatment. Depleting DRG2 in melanoma cells enhanced IFN-γ signaling and increased PD-L1 expression. However, it disrupted the recycling of endosomal PD-L1, reducing its levels on the cell surface and impairing its interaction with PD-1. As a result, anti-PD-1 therapy failed to expand effector-like PARP/HDAC-IN-1 T cells in DRG2-depleted tumors and did not improve the survival of mice with DRG2-depleted tumors. An analysis of a patient cohort revealed that melanoma patients with low DRG2 protein levels were resistant to anti-PD-1 therapy. These findings highlight DRG2 as a critical regulator of endosomal PD-L1 recycling and tumor response to anti-PD-1 therapy, offering new insights into enhancing the link between PD-L1 expression and treatment response.