PIKfyve inhibition enhances antitumor immune responses via SNX17-Retriever-mediated endocytic recycling of MHC-I

ABSTRACT: Tumor cells frequently down‑regulate surface MHC‑I to evade immune surveillance. Therapeutic approaches that up‑regulate MHC‑I hold promise for restoring effective CD8⁺ T‑cell monitoring and enhancing checkpoint‑blockade therapy efficacy. Inhibition of PIKfyve—a kinase that converts PI3P to PI(3,5)P₂ and governs endosomal‑lysosomal trafficking—restores MHC‑I surface expression, yet its mechanistic basis remained unclear. Here we identify XMU‑MP‑7, a potent PIKfyve inhibitor, which markedly elevates surface MHC‑I levels and immunopeptides abundance by blocking autophagic flux, sequestering MHC‑I in Rab5-positive endosomes, and activating SNX17‑Retriever‑mediated recycling of MHC-I to the plasma membrane. XMU‑MP‑7 enhances CD8⁺ T‑cell cytotoxicity and shows robust antitumor activity in syngeneic mouse models. Moreover, it synergizes with immune‑checkpoint blockade therapy, especially in tumors with KRAS mutations. These findings clarify the mechanism by which PIKfyve inhibition up-regulates MHC-I and position XMU-MP-7 as a promising adjunct to immunotherapy.

INSTRUMENT(S):

ORGANISM(S): Homo Sapiens

TISSUE(S): Pancreatic Cancer Cell

SUBMITTER: Chenxi Yang  

LAB HEAD: Deng Xianming

PROVIDER: PXD085263 | Pride | 2026-10-29

REPOSITORIES: Pride