Temporal Immune and Metabolic Shifts Drive the Anti‐Tumor Efficacy of Resiquimod‐Loaded Nanoparticles in Peritoneal Carcinomatosis

ABSTRACT Peritoneal carcinomatosis (PC) is an aggressive manifestation of advanced gynecological and gastrointestinal malignancies with high recurrence rates despite cytoreductive surgery and chemotherapy. We developed a cationic liposomal nanoparticle (DSTAP, ∼159 nm) to deliver and retain the toll‐like receptor 7/8 agonist Resiquimod (R848) within the peritoneal cavity, aiming to modulate the tumor immune microenvironment (TIME) and improve therapeutic efficacy. DSTAP‐R848 was evaluated in murine colorectal and ovarian PC models, alone or combined with oxaliplatin (Oxa). Survival, cure rates, and durable immunity following tumor rechallenge were assessed. Immune polarization was examined by incubating ascites and peritoneal fluid with naïve splenocytes, while flow cytometry and metabolomic profiling characterized intratumoral immune populations and metabolic changes. Combination therapy achieved cure rates of 80% in the colorectal model and 30% in the ovarian model, with no recurrence after rechallenge; Oxa monotherapy yielded no cures. Oxa+DSTAP‐R848 increased CD8 + T cells and M1 macrophages, while reducing regulatory T cells and myeloid‐derived suppressor cells. Immunosuppressive and glycolytic metabolites progressively declined, correlating with reduced tumor burden. Overall, DSTAP‐R848 enhances chemotherapy efficacy by reshaping immune and metabolic pathways and promoting durable anti‐tumor immunity in PC.