Stromal\nReprogramming Optimizes KRAS-Specific Chemotherapy\nInducing Antitumor Immunity in Pancreatic Cancer

Pancreatic ductal adenocarcinoma\n(PDAC) is a clinically challenging\ncancer and is often characterized with rich stroma and mutated KRAS,\nwhich determines the tumor microenvironment (TME) and therapy response.\nTurning immunologically “cold” PDAC into “hot”\nis an unmet need to improve the therapeutic outcome. Herein, we propose\na programmable strategy by sequential delivery of pirfenidone (PFD)\nand nanoengineered KRAS specific inhibitor (AMG510) and gemcitabine\n(GEM) liposomes. PFD could achieve precise reduction of the extracellular\nmatrix (ECM) by reprogramming pancreatic stellate cells (PSCs). Subsequently,\ntargeting the KRAS-directed oncogenic signaling pathway effectively\ninhibited tumor proliferation and migration, which sensitized a chemotherapeutic\ndrug and promoted immunogenic cell death (ICD). In preclinical mouse\nmodels of PDAC, PFD mediated stromal modulation enhanced the deep\npenetration of nanoparticles and improved their subsequent performance\nin tumor growth inhibition. The molecular mechanisms elucidated that\nthe stroma intervention and KRAS signal pathway regulation reshaped\nthe immunosuppression of PDAC and optimized cytotoxic T-cell-mediated\nantitumor immunity with sustained antitumor memory. Overall, our\nstudy provides a practical strategy with clinical translational promise\nfor immunologically cold tumor PDAC treatment.