Fig. 8: Mechanistic model of Munc13-4-mediated tumor immune evasion through the regulation of PD-L1 sorting and secretion via exosomes.
From: Munc13-4 mediates tumor immune evasion by regulating the sorting and secretion of PD-L1 via exosomes
Schematic illustration showing that Munc13-4 collaborates with HRS, Rab27, and SNAREs to regulate PD-L1 sorting and secretion via exosomes. Loss of Munc13-4 in breast tumors enhances T cell-mediated anti-tumor immunity, suppresses tumor growth, and improves the efficacy of immune checkpoint inhibitors. Mechanistically, Munc13-4 regulates PD-L1 sorting by forming a ternary complex with PD-L1 and HRS. IFNγ stimulation modifies Munc13-4 and HRS, establishing a dynamic regulatory mechanism that enables tumor cells to adapt to immune pressure by modulating exosomal PD-L1 sorting. Downstream of sorting, Munc13-4 engages Rab27a to regulate MVB tethering and promotes SNARE complex assembly, thereby facilitating MVB–plasma membrane fusion and exosome release. Therapeutically, a designed peptide that disrupts the Munc13-4–PD-L1 interaction impairs PD-L1 sorting, resulting in enhanced anti-tumor immunity and reduced tumor growth in vivo.
