Abstract This study investigates the use of an immunotherapeutic plant virus, namely the cowpea mosaic virus (CPMV), that when used prophylactically and therapeutically can protect against metastatic cancer in multiple tumor mouse models. Metastatic cancer continues to be the main cause of death of most cancer patients, and new treatment modalities must be engineered to protect patients from metastatic disease. For instance, peritoneal metastases (PMs) are oftentimes fatal, and patients survive for a median 6 months following diagnosis. PMs are common for colon, ovarian, gastric, appendiceal, and pancreatic cancers. Previously, it was demonstrated that CPMV is a potent in situ vaccine causing tumor shrinkage with abscopal effect and long-term protection observed in tumor mouse models and canine cancer patients. CPMV functions as a toll like receptor (TLR) agonist and acts on innate immune cells to induce tumor cell killing and antigen processing to eventually prime adaptative and tumor-specific immunity. However, metastatic cancers such as PMs are not easily and directly injectable and therefore, we have expanded the ability of CPMV to protect against PMs by engineering targeted CPMV nanoparticles. Data indicates that CPMV can improve survival and slow tumor growth in a murine colon PM model compared to controls and that long-term survivors are further protected from re-challenge indicating tumor specificity. Analysis from current and past studies indicate that CPMV injection into the intraperitoneal space leads to distinct upregulation of immunostimulatory cytokines and recruitment of innate immune cell populations. PMs lead to extreme declines in quality of life of patients, and current treatments can be ineffective in slowing down or reducing tumor development and death - in tackling this problem, the data clearly points to the strong potential for CPMV-mediated therapeutics in the treatment and prophylaxis of PMs. Dr. Steinmetz is a co-founder of and has a financial interest in Mosaic ImmunoEngineering Inc. The other authors have no conflict of interest to declare. Acknowledgments: This work is supported in part through NIH grants R01 CA274640, R01 CA224605, R01 CA253615, CDMRP W81XWH2010742, and the Shaughnessy Family Fund for Nano-ImmunoEngineering (nanoIE at UC San Diego). Citation Format: Young Hun Chung, Britney A. Volckaert, Nicole F. Steinmetz. Treatment of metastatic cancers using immunotherapeutic cowpea mosaic virus nanoparticles [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 812.