ULK1 Knockout suppresses Pancreatic Cancer Progression by Inhibiting Autophagy and Enhancing Anti-tumor Immunity

Autophagy plays a dual role in cancer, acting as a tumor suppressor and promoter depending on tumor stage and context. While core autophagy genes such as Atg5 and Atg7, the role of Unc-51-like kinase 1 (ULK1) —a key autophagy initiator-remains poorly understood in pancreatic ductal adenocarcinoma (PDAC). In this study, we investigated the role of ULK1 using tissue-specific deletion in GEM models. Although ULK1 mRNA levels remained unchanged between normal and tumor cells in The Cancer Genome Atlas (TCGA) dataset, multiplex immunohistochemistry revealed elevated ULK1 activity, marked by phosphorylated ATG14, in high-grade human PDAC tissues. Genetic deletion of Ulk1 impaired autophagy, reduced cell proliferation, colony formation, and invasiveness of pancreatic cancer cells. In vivo both syngeneic orthotopic and KPC (LSL-KrasG12D/+; LSL-Trp53R172H/+; Pdx1-Cre) mouse model 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 (PMN-MDSCs) and neutrophils while enhancing recruitment of cytotoxic CD8+ T cells and MHC-II+ antigen-presenting cells. Chemokine and cytokine profiling revealed that downregulation of Cxcl2, Ccl2, and G-CSF, might acting for PMN-MDSCs and neutrophils recruitment and survival, with concurrent upregulation of GM-CSF for dendritic cell infiltration, thereby inducing antitumor immunity. These findings provide novel 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.