Stromal Reprogramming Optimizes KRAS-Specific Chemotherapy Inducing Antitumor Immunity in Pancreatic Cancer

Pancreatic ductal adenocarcinoma (PDAC) is a clinically challenging cancer and is often characterized with rich stroma and mutated KRAS, which determines the tumor microenvironment (TME) and therapy response. Turning immunologically "cold" PDAC into "hot" is an unmet need to improve the therapeutic outcome. Herein, we propose a programmable strategy by sequential delivery of pirfenidone (PFD) and nanoengineered KRAS specific inhibitor (AMG510) and gemcitabine (GEM) liposomes. PFD could achieve precise reduction of the extracellular matrix (ECM) by reprogramming pancreatic stellate cells (PSCs). Subsequently, targeting the KRAS-directed oncogenic signaling pathway effectively inhibited tumor proliferation and migration, which sensitized a chemotherapeutic drug and promoted immunogenic cell death (ICD). In preclinical mouse models of PDAC, PFD mediated stromal modulation enhanced the deep penetration of nanoparticles and improved their subsequent performance in tumor growth inhibition. The molecular mechanisms elucidated that the stroma intervention and KRAS signal pathway regulation reshaped the immunosuppression of PDAC and optimized cytotoxic T-cell-mediated antitumor immunity with sustained antitumor memory. Overall, our study provides a practical strategy with clinical translational promise for immunologically cold tumor PDAC treatment.