In mouse studies, the weight‑loss drug retatrutide not only shrank body fat but also dramatically slowed the growth of pancreatic and lung cancers linked to obesity. Even after the drug was stopped, the anti‑cancer effects stuck around, likely because it reshaped the immune system to be more anti‑tumor.

Medical therapeutics for weight loss are changing the landscape of obesity but impacts on obesity-associated cancer remain unclear. We report that in pre-clinical models with significant retatrutide (RETA, LY3437943)-induced weight loss, pancreatic cancer engraftment was reduced, tumor onset was delayed, and progression was attenuated resulting in a 14-fold reduction in tumor volume compared to only 4-fold reduction in single agonist semaglutide-treated mice. Despite weight re-gain after RETA withdrawal, the anti-tumor benefits of RETA persisted. Remarkably, RETA-induced protection extends to a lung cancer model with 50% reduced tumor engraftment, significantly delayed tumor onset, and mitigated tumor progression, with a 17-fold reduction in tumor volume compared to controls. RETA induced immune reprogramming systemically and in the tumor microenvironment with durable anti-tumor immunity evidenced by elevated circulating IL-6, increased antigen presenting cells, reduced immunosuppressive cells, and activation of pro-inflammatory pathways. In sum, our findings suggest that patients with RETA-mediated weight loss may also benefit from reduced cancer risk and improved outcomes.