{
  "abstract": "Background Medical therapies for weight loss are transforming obesity management; however, their impact on obesity-associated cancers such as pancreatic ductal adenocarcinoma (PDAC) remains poorly understood. We previously demonstrated in preclinical models that the triple incretin agonist retatrutide (RETA, LY3437943) significantly reduced PDAC tumor burden, yielding a 14-fold reduction in tumor volume compared to a 4-fold reduction with the single GLP-1 receptor agonist semaglutide. Remarkably, the anti-tumor effects of RETA persisted after treatment discontinuation and weight regain, suggesting tumor-intrinsic or immunometabolic mechanisms independent of weight loss. 1 Motivated by these findings, we investigated whether RETA administered at a subtherapeutic dose insufficient to induce weight loss could achieve anti-tumor efficacy comparable to anti-PD-1 therapy.Methods Subcutaneous tumors were established using KPCY-derived PDAC cells in diet-induced obese C57BL/6J male mice. Animals were randomized into four groups (N=10/group): vehicle control (sterile water), RETA (s.q., 1 nmol/kg), anti-PD-1 (i.p., 10 mg/kg), or the combination of RETA and anti-PD-1. Treatments were administered every three days for two weeks, beginning post-tumor cell injection. Tumor growth was assessed using digital calipers, and splenic immune profiling was performed at endpoint via high-dimensional spectral flow cytometry.Results Low-dose RETA significantly reduced tumor volume by 3-fold compared to vehicle, demonstrating efficacy comparable to anti-PD-1 monotherapy, which achieved a 5-fold reduction in tumor volume. With a 4-fold reduction in tumor volume, RETA + anti-PD-1 combination therapy did not demonstrate significant additional benefit beyond either monotherapy. Importantly, body weight remained stable across all groups, while blood glucose levels were significantly lowered by RETA treatment, indicating RETA’s anti-tumor effects occurred independently of weight loss and may involve metabolic modulation.Conclusions Findings demonstrate that low-dose RETA exerted anti-tumor effects comparable to anti-PD-1 immunotherapy in a preclinical pancreatic cancer model, independent of weight loss. Ongoing studies in additional models aim to determine mechanisms mediating RETA’s potent anti-tumor function. RETA may have direct anti-tumor and/or anti-tumor immunity actions that contribute to improved tumor outcomes. Further exploration of RETA as a novel therapeutic strategy for obesity-associated cancers are warranted.Reference Marathe SJ, Grey EW, Bohm MS, Joseph SC, Ramesh AV, Cottam MA, Idrees K, Wellen KE, Hasty AH, Rathmell JC, Makowski L. Incretin triple agonist retatrutide (LY3437943) alleviates obesity-associated cancer progression. NPJ Metab Health Dis. 2025;3:10.",
  "authors": [
    {
      "affiliations": [
        "The University of Tennessee Health Science Center, Memphis, TN, USA"
      ],
      "name": "Sandesh J Marathe"
    },
    {
      "affiliations": [
        "The University of Tennessee Health Science Center, Memphis, TN, USA"
      ],
      "name": "Margaret S Bohm"
    },
    {
      "affiliations": [
        "The University of Tennessee Health Science Center, Memphis, TN, USA"
      ],
      "name": "Zereque Powell"
    },
    {
      "affiliations": [
        "The University of Tennessee Health Science Center, Memphis, TN, USA"
      ],
      "name": "Areej Khan"
    },
    {
      "affiliations": [
        "The University of Tennessee Health Science Center, Memphis, TN, USA"
      ],
      "name": "Naveed Pervaiz"
    },
    {
      "affiliations": [
        "University of Pennsylvania, Philadelphia, PA, USA"
      ],
      "name": "Kathryn E Wellen"
    },
    {
      "affiliations": [
        "The University of Chicago, Chicago, IL, USA"
      ],
      "name": "Jeffrey C Rathmell"
    },
    {
      "affiliations": [
        "The University of Tennessee Health Science Center, Memphis, TN, USA"
      ],
      "name": "Liza Makowski"
    }
  ],
  "title": "661 Retatrutide monotherapy matches the effectiveness of anti-PD-1 immunotherapy in a preclinical model of pancreatic cancer",
  "uid": "543f60bc-264b-5c02-a6f4-230036ac8331"
}