ULK1 knockout suppresses pancreatic cancer progression by inhibiting autophagy and enhancing antitumor immunity.

Autophagy plays a dual role in cancer, acting as a tumor suppressor and promoter depending on tumor stage and context. While Atg5 and Atg7 are well established core autophagy genes, the role of Unc-51-like kinase 1 (ULK1)-a key autophagy initiator-remains poorly understood in pancreatic ductal adenocarcinoma (PDAC). Here we investigated the role of ULK1 using tissue-specific deletion in genetically engineered mouse models. Although ULK1 messenger RNA levels remained unchanged between normal and tumor cells in The Cancer Genome Atlas dataset, multiplex immunohistochemistry revealed elevated ULK1 activity, marked by pATG14, in high-grade human PDAC tissues. Genetic deletion of Ulk1 impaired autophagy and reduced cell proliferation, colony formation and invasiveness of pancreatic cancer cells. In vivo, both syngeneic orthotopic and KPC (LSL-Kras; LSL-Trp53; Pdx1-Cre) mouse models with tissue-specific Ulk1 deletion exhibited significant delayed tumor progression, reduced tumor burden and extended survival. Importantly, Ulk1 deficiency remodeled the tumor immune microenvironment by reducing tumor-promoting polymorphonuclear myeloid-derived suppressor cells and neutrophils while substantially enhancing recruitment of cytotoxic CD8 T cells and major histocompatibility complex II antigen-presenting cells. Chemokine and cytokine profiling revealed that downregulation of Cxcl2, Ccl2 and G-CSF might lead to polymorphonuclear myeloid-derived suppressor cell and neutrophil recruitment and survival, with concurrent upregulation of GM-CSF for dendritic cell infiltration, thereby inducing antitumor immunity. These findings provide insights into the role of ULK1 in PDAC progression through tumor-intrinsic metabolic support by autophagy activation and immune modulation by tumor-derived cytokines. Targeting ULK1 may represent a promising therapeutic strategy by inhibiting autophagy and enhancing antitumor immune responses in pancreatic cancer.