Abstract
Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal malignancy with pronounced resistance to conventional therapies. Irreversible electroporation (IRE) is a promising therapy for PDAC; however, its clinical efficacy is limited by a high recurrence rate. Here, using a preclinical PDAC model, we characterized the tumor immune microenvironment following insufficient IRE (iIRE) through single-cell RNA sequencing. We found that iIRE induces a CCR2+ tumor-associated macrophage (CCR2+ TAM)-mediated immunosuppressive microenvironment in residual tumors. Consequently, we developed a macrophage-based proteolipid vesicle (mPLV) coencapsulating the CCR2 antagonist PF-4136309 (PF) and gemcitabine (GEM), named PF/GEM@mPLV. Our findings suggest that PF/GEM@mPLV achieves high drug accumulation within tumors through iIRE-induced inflammation. Reduction of CCR2+ TAMs enhances antitumor immunity and improves chemotherapeutic response. PF/GEM@mPLV markedly inhibits tumor recurrence following iIRE, diminishes hepatic metastases, and prolongs survival in preclinical PDAC models. These findings uncover the role of CCR2+ TAMs in iIRE-induced immunosuppression, offering a promising strategy to enhance the clinical potential of IRE in PDAC.