MFGE8 induces anti-PD-1 therapy resistance by promoting extracellular vesicle sorting of PD-L1.

ABSTRACT: Anti-PD-1 therapy, effective in patients with various advanced tumors, still encounters the challenge of insensitivity in most patients. Here, we demonstrate that PD-L1 on tumor cell-derived extracellular vesicles (TEVs) is critical for anti-PD-1 therapy resistance. Reducing endogenous and transferring exogenous TEVs abrogates and induces anti-PD-1 therapy resistance, respectively. Notably, PD-L1 is sorted onto TEVs via the endosomal sorting complex required for transport after ubiquitination by UBE4A and gradually upregulated on TEVs with tumor progression. During progression, increased MFGE8 from tumor cells promotes self α_v integrin signaling activation, enabling themselves to upregulate UBE4A, thereby increasing PD-L1 on TEVs and enhancing their immunosuppressive abilities.

SUBMITTER: Wang W 

PROVIDER: S-EPMC11866489 | biostudies-literature | 2025 Feb

REPOSITORIES: biostudies-literature