Targeting Splenic Myeloid Cells with Nanobiologics to Prevent Postablative Pancreatic Cancer Recurrence via Inducing Antitumor Peripheral Trained Immunity

Abstract Minimally invasive irreversible electroporation ablation shows promise for pancreatic cancer (PCa), but the high recurrence and metastasis rates pose a therapeutic challenge for loco‐regional ablation treatment. Immunotherapy holds promise for preventing tumor recurrence, however, its efficacy against PCa remains limited. Here, using a preclinical model of PCa, it is identified that tumor development dramatically restructures the splenic immune landscape characterized by increased frequency of myeloid cells. Further, nanobiologics with high affinity for splenic myeloid cells using erythrocyte membrane fused with apoA1‐modified liposomes are presented. Biocompatible CaCO 3 nanoparticles are incorporated to serve as a release reservoir of immunomodulatory therapeutics (muramyl dipeptide, MDP). The nanobiologics, MDCa@RBC‐Alipo, induce antitumor‐trained immunity by epigenetically and metabolically rewiring splenic myeloid cells, thereby overcoming the immunosuppressive tumor microenvironment in residual PCa following irreversible electroporation ablation. This approach enhances the therapeutic efficacy of aPD‐L1 and significantly inhibits tumor recurrence and hemorrhagic ascites development. The trafficking of MDP directly to the spleen highlights a previously uncharacterized pathway for inducing peripheral trained immunity, thereby presenting a novel therapeutic approach for locally advanced PCa treatment.