PARP2 deficiency impairs pancreatic cancer progression by promoting genomic instability and antitumor immunity
Menée à l'aide de lignées cellulaires, de modèles murins d'adénocarcinome canalaire du pancréas et d'échantillons de tissus pancréatiques d'origine humaine, cette étude met en évidence un mécanisme par lequel une déficience de la polymérase PARP2 retarde la progression tumorale en augmentant le stress réplicatif et en stimulant l'immunité antitumorale
Pancreatic cancer represents one of the most lethal tumors, characterized by an immunosuppressive microenvironment and a lack of cytotoxic immune cell infiltrates, which confer resistance to immunotherapy. Here, we demonstrate that deletion of poly(ADP-ribose) polymerase 2 (PARP2) in a Myc-driven mouse model of pancreatic cancer delays tumor progression and increases survival. Mechanistically, PARP2 loss induces enrichment of pathways associated with genomic instability and replicative stress, leading to increased γH2AX, chromosomal instability, and micronuclei accumulation. In addition to these tumor-intrinsic effects, PARP2 deletion reshapes the tumor microenvironment, promoting infiltration of cytotoxic T and natural killer cells while reducing immunosuppressive cell populations, enhancing antitumor cytotoxicity. These findings are recapitulated in a KrasG12D-driven orthotopic pancreatic ductal adenocarcinoma model. Collectively, our data support selective PARP2 inhibition as a promising therapeutic strategy for pancreatic cancer by impairing genome integrity and boosting antitumor immune response, thereby opening potential avenues for combating this devastating disease. PARP2 deficiency hampers pancreatic cancer progression by increasing replicative stress and unleashing antitumor immunity.
Science Advances , article en libre accès, 2026