Receptor-interacting protein kinase 2 is an immunotherapy target in pancreatic cancer.

Pancreatic ductal adenocarcinoma (PDAC) remains a highly lethal malignancies due to its aggressive nature and the paucity of effective treatment options. Almost all registered drugs have proven ineffective in addressing the needs of PDAC patients. This is the result of a poor understanding of the unique tumor immune microenvironment (TME) in PDAC. To identify druggable regulators of immunosuppressive TME, we performed a kinome- and membranome-focused CRISPR screening using orthotopic PDAC models. Our data showed that RIPK2 is a crucial driver of immune evasion of cytotoxic T-cell killing and that genetic or pharmacological targeting of RIPK2 sensitizes PDAC to anti-PD-1 immunotherapy, leading to prolonged survival or complete regression. Mechanistic studies revealed that tumor-intrinsic RIPK2 ablation disrupts desmoplastic TME and restores MHC-I surface levels through eliminating NBR1-mediated autophagy-lysosomal degradation. Our results provide a rationale for a novel combination therapy consisting of RIPK2 inhibition and anti-PD-1 immunotherapy for PDAC.