Abstract 6669: Vagal perturbation of the gut-brain axis deters cancer-associated cachexia

Abstract Cancer-associated cachexia (CAC) is a wasting syndrome present in 80% of advanced cancer patients. CAC decreases the quality of life, causes higher mortality, and causes resistance to treatments with increased toxicity. CAC is currently incurable and directly responsible for up to 30% of all cancer deaths. We find that cancer-induced systemic inflammation disrupts vagal tone via infiltration of innate immune cells into the brain, involving the vagal dorsal motor nucleus of the hindbrain. This disruption leads to CCL2-driven vagal hyperactivation and elevated acetylcholine output to the liver, resulting in the downregulation of hepatocyte nuclear factor 4 alpha (HNF4α), a key regulator of liver metabolism. We further demonstrate that a right cervical vagotomy in mice with lung or pancreatic cancer disrupts the abnormal CNS-liver vagal crosstalk, restoring liver metabolism and feeding behavior, thereby alleviating cachexia symptoms independent of tumor burden. Importantly, electrical, chemical, or surgical disruption of the right vagus nerve, including via a custom wireless implantable device, restores liver metabolism, alleviates CAC manifestations, and synergizes with chemotherapy, significantly improving the overall well-being and survival rates of mice with lung or pancreatic cancer. Our findings have substantial translational potential for CAC treatment, mainly as non-invasive vagal interventions are already FDA-approved for other therapeutic applications. Citation Format: Aliesha D. Garrett, Xiling Shen, Ayelet Erez, Naama Darzi. Vagal perturbation of the gut-brain axis deters cancer-associated cachexia [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 6669.