MLKL/retromer axis controls PD-L1 recycling to compromise antitumor immunity during VCP inhibition–induced necroptosis

The activation of the vesicular trafficking system, including endosomal recycling and extracellular vesicle (EV) release, represents an adaptive mechanism in cancer cells to counteract cellular stress or necroptotic death signals, which hampers cancer therapy. However, the underlying mechanisms remain poorly understood. Indeed, our study demonstrate that inhibition of valosin-containing protein (VCPi) induces EV release and necroptosis in colorectal cancer (CRC), but does not achieve a synergistic effect with immunotherapy. Mechanistically, VCPi delays the degradation of mixed lineage kinase domain-like protein (MLKL), a critical regulator of necroptosis and endosomal trafficking. Knockdown of MLKL reduces VCPi-mediated necroptosis, EV release, and programmed death ligand 1 (PD-L1) recycling. VCPi leads to MLKL accumulation, which recruits the retromer complex and GTPase-activating protein TBC1D5 to inactivate Rab7A. This redirects PD-L1-loaded vesicles to the cell surface via the retromer complex, thereby resulting in immunosuppression. Notably, targeting the retromer complex enhances the therapeutic efficacy of combined VCP inhibitors and anti-PD-L1 therapy in CRC, offering a promising immunotherapeutic strategy. Our study elucidates the role of the retromer complex in mediating PD-L1 recycling during VCPi-induced necroptosis and reveals that dual inhibition of VCP and the retromer complex potentiates immunotherapy efficacy in CRC.