Biomimetic Nanoplatform for Fibrosis Remodeling and Anti‐PD‐1 Potentiation via Cu + /Ca 2+ Ion Dysregulation and TGF‐β Inhibition in PDAC

ABSTRACT Pancreatic ductal adenocarcinoma (PDAC) remains refractory to immunotherapy, largely due to the dense fibrotic stroma that promotes immune evasion and restricts drug penetration. Here, we report a multifunctional biomimetic nanoplatform (RPm@CC‐LY) that simultaneously remodels the fibrotic tumor microenvironment and potentiates antitumor immunity. RPm@CC‐LY achieves efficient tumor accumulation and effectively attenuates fibrosis through sustained release of Transforming growth factor‐β (TGF‐β) inhibitor LY2157299 (LY). Concurrently, intracellular acid‐triggered degradation induces Cu + ‐mediated Fenton‐like reactions and Ca 2+ overload, leading to oxidative stress, mitochondrial dysfunction, and tumor cell apoptosis. In parallel, RPm@CC‐LY reprograms tumor‐associated macrophages (TAMs) toward an M1 phenotype and enhances dendritic cell maturation, thereby promoting robust CD8 + T cell infiltration. Notably, when combined with anti–PD‐1 (αPD1) therapy, RPm@CC‐LY induces a systemic immune response in mice. This work establishes a synergistic nanotherapeutic strategy that integrates fibrosis remodeling with ion interference therapy to overcome the immunotherapeutic barriers posed by fibrosis in PDAC.