STAM2-mediated fine-tuning of PD-L1 secretion via small extracellular vesicles in oral squamous cell carcinoma

The secretion of programmed death ligand 1 (PD-L1) via small extracellular vesicles (sEVs) endows this immune checkpoint protein with diverse and systemic roles. This intercellular communication mediated by sEV PD-L1 not only fosters a pro-tumorigenic niche but also induces systematic immunosuppression. Revealing the intricate mechanisms underlying sEV PD-L1 secretion is essential for understanding tumor pathology and developing targeted therapies. Here, we demonstrated the specialization and collaboration among members of the endosomal sorting complex required for transport-0 (ESCRT-0) family in regulating sEV PD-L1 secretion in oral squamous cell carcinoma (OSCC). Mechanistically, STAM2, not STAM1, directly binds cell surface PD-L1, followed by recruiting HRS to initiate the biogenesis of PD-L1⁺ sEVs. Specifically, STAM2 binds the functional domains of PD-L1 and HRS through the VHS and ITAM domains respectively, acting as a molecular bridge between PD-L1 and HRS. Therefore, our study delineated the sequential participation of different ESCRT-0 members during sEV PD-L1 secretion and highlighted the pivotal role of STAM2 in orchestrating this process, providing important insights into diseases with aberrant PD-L1 secretion, such as OSCC.