Plasma-activated solutions potentiate the antitumor effects of HIPEC via endoplasmic reticulum stress mediated apoptosis.

Hyperthermic intraperitoneal chemotherapy (HIPEC) is a promising therapy for peritoneal metastasis, yet variable efficacy and complications necessitate improvement. This study investigates plasma-activated solutions (PAS) as an enhancer of HIPEC against colorectal cancer-derived peritoneal metastasis. Using murine models and human colorectal cancer cell lines, PAS combined with HIPEC significantly suppresses tumor growth, reduces malignant ascites, and improves survival. Mechanistically, PAS induces oxidative stress, activating the endoplasmic reticulum stress (ER-stress) pathway to trigger cancer cell death. Reactive oxygen species (ROS) are critical mediators, as their neutralization abolishes antitumor effects. Furthermore, integrating PAS-HIPEC with anti-PD-L1 immunotherapy yields synergistic tumor control and survival benefits superior to monotherapies. These findings establish PAS-enhanced HIPEC as a promising strategy that leverages ROS-mediated cell death to potentiate chemotherapy and sensitize tumors to immunotherapy, offering a novel approach for this challenging disease.