2. Academic Validation
  3. Incretin triple agonist retatrutide (LY3437943) alleviates obesity-associated cancer progression

Incretin triple agonist retatrutide (LY3437943) alleviates obesity-associated cancer progression

  • NPJ Metab Health Dis. 2025;3(1):10. doi: 10.1038/s44324-025-00054-5.
Sandesh J Marathe 1 2,  Emily W Grey 1,  Margaret S Bohm 3,  Sydney C Joseph 1,  Arvind V Ramesh 1,  Matthew A Cottam 4,  Kamran Idrees 4,  Kathryn E Wellen 5,  Alyssa H Hasty 6,  Jeffrey C Rathmell 7 8,  Liza Makowski 1 2 3
Affiliations

Affiliations

  • 1 Department of Medicine, Division of Hematology and Oncology, College of Medicine, The University of Tennessee Health Science Center, Memphis, TN USA.
  • 2 UTHSC Center for Cancer Research, College of Medicine, The University of Tennessee Health Science Center, Memphis, TN USA.
  • 3 Department of Microbiology, Immunology, and Biochemistry, College of Medicine, The University of Tennessee Health Science Center, Memphis, TN USA.
  • 4 Division of Surgical Oncology, Department of Surgery, Vanderbilt University Medical Center, Nashville, TN USA.
  • 5 Department of Cancer Biology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA USA.
  • 6 Department of Internal Medicine, Touchstone Diabetes Center, UT Southwestern, Dallas, TX USA.
  • 7 Vanderbilt Center for Immunobiology, Vanderbilt University Medical Center, Nashville, TN USA.
  • 8 Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, TN USA.
PMID: 40094000 DOI: 10.1038/s44324-025-00054-5
Abstract

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.

Keywords

Cancer; Endocrine system and metabolic diseases; Obesity.

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