TGF-β-Targeting Platinum(IV) Prodrugs Remodel Tumor Microenvironment of Pancreatic Cancer via Antifibrotic and Immunomodulatory Effects

Abstract Pancreatic ductal adenocarcinoma (PDAC) features dense desmoplastic stroma that impedes drug penetration and immune infiltration, and promotes therapeutic resistance. As a central driver of stromal fibrosis and immunosuppression, TGF-β represents an attractive target for overcoming these barriers. Herein, we report novel Pt(IV) prodrugs conjugated with TGF-β inhibitors (hydronidone/4-hydroxyphenylacetic acid), which simultaneously achieve chemotherapy and tumor microenvironment remodeling. Biological screening identified HP-12C and AP as lead compounds with tumor-selective cytotoxicity and substantial activity in patient-derived organoids. In vitro, these prodrugs suppressed tumor-cell-derived TGF-β-associated profibrotic signaling, attenuated cancer-associated fibroblasts (CAFs) activation, improved platinum penetration across a fibrotic barrier model; and partially relieved tumor-mediated immunosuppression in PBMC co-culture assays. In vivo, HP-12C showed superior tumor accumulation and antitumor efficacy, reduced fibrosis, favorable tolerability relative to conventional platinum drugs, and increased CD8+ T-cell infiltration. Collectively, these findings identify TGF-β-modulated Pt(IV) prodrugs as a promising chemotherapy strategy to overcome fibrosis and immunosuppressive barriers in PDAC.