PD-L1 in tumor-derived extracellular vesicles promotes T-cell senescence and suppression of tumor immunity 4555

Description Tumor-derived extracellular vesicles (tEVs) play a pivotal role in immune suppression within the tumor microenvironment (TME) by inducing T-cell senescence, a novel mechanism of dysfunction distinct from exhaustion. Here, we identify programmed death-ligand 1 (PD-L1) as a critical component of tEVs that promotes T-cell senescence through activation of the ATM-associated DNA damage response and subsequent CREB and STAT1/3 signaling. Functionally, tEVs suppress T-cell proliferation and effector activity, thereby contributing to resistance against immune checkpoint blockade therapies. Using in vitro and in vivo melanoma models, we demonstrate that targeting PD-L1, or inhibiting CREB signaling reverses T-cell senescence and enhances anti-tumor immunity. Furthermore, combining this strategy with immune checkpoint inhibitors significantly improves therapeutic efficacy. This study uncovers a novel molecular mechanism underlying tEV-mediated immunosuppression and provides a foundation for innovative combination therapies to overcome resistance and improve cancer immunotherapy outcomes. Funding Sources This work was partially supported by grants from the Melanoma Research Alliance (No. 621833 to G. P) and the NIH (CA184379, CA242188, CA237149, AI173260, AG078822, and AG067441 to G. P; GM128047 and GM141652 to Y. W).