Targeting the UFL1-PARP1 axis amplifies anti-tumor immunity.

Cancer immunotherapies are widely used to treat various cancers but are largely ineffective against pancreatic ductal adenocarcinoma (PDAC), with the underlying mechanisms poorly understood. UFMylation, a ubiquitin-like modification, regulates diverse biological and pathological processes, yet its role in PDAC remains unclear. This study reports that UFMylation drives PDAC growth and resistance to cancer immunotherapy. Mechanistically, the E3 ligase UFL1 facilitates PARP1 UFMylation, preventing its ubiquitination and degradation. Stabilized PARP1 enhances DNA damage repair, suppresses R-loop formation, and inhibits cyclic guanosine monophosphate-adenosine monophosphate synthase (cGAS)-stimulator of interferon gene (STING) activation, thereby promoting tumor immune evasion. In contrast, inhibiting UFMylation reverses these effects, facilitating tumor infiltration of cytotoxic CD8 T cells and improving the efficacy of anti-PD-1 immunotherapy in the pancreatic tumor model. Clinically, UFL1 protein levels are positively correlated with PARP1 and inversely correlated with cGAS-STING activation and CD8 T cell infiltration in PDAC. These findings highlight UFMylation as a promising therapeutic target to enhance immunotherapy in PDAC.