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Figure 2 from Sucralose Consumption Ablates Cancer Immunotherapy Response through Microbiome Disruption

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posted on 2025-11-03, 08:25 authored by Kristin M. Morder, Madison Nguyen, Drew N. Wilfahrt, Zakaria Larbi Dahmani, Ansen B.P. Burr, Bingxian Xie, Michael Morikone, Hector Nieves-Rosado, William G. Gunn, Drew E. Hurd, Hong Wang, Steven J. Mullett, Kaitlin Bossong, Stacy L. Gelhaus, Dhivyaa Rajasundaram, Lawrence P. Kane, Greg M. Delgoffe, Jishnu Das, Diwakar Davar, Abigail E. Overacre-Delgoffe
<p>Sucralose ablates immunotherapeutic responses. C57BL/6 mice from Taconic consumed sucralose in the drinking water (0.09 mg/mL) for 2 weeks prior to tumor injection and for the duration of the experiment. Mice were injected with 2.5 × 10<sup>5</sup> MC38 cells subcutaneously and treated with 200 µg anti–PD-1 on days 9, 12, and 15. Tumor area was measured every 3 days until endpoint. <b>A,</b> Experimental schematic. <b>B,</b> Tumor growth curves of mice consuming sucrose or sucralose in the drinking water during treatment with anti–PD-1. CR, complete response. <b>C,</b> Tumor growth curves in MC38 subcutaneous (circles) or B16 intradermal (squares) treated with anti–PD-1. Mice were sourced from either The Jackson Laboratory (Jax, open circles) or Taconic Biosciences (Taconic, closed circles). Mice were removed from study either when tumors reached 2 cm in either direction or if there was unresolved ulceration. Mean tumor growth lines halt once all mice in a treatment group were removed. <b>D</b> and <b>E,</b> C57BL/6 mice from either Taconic (<b>D</b>) or Jackson (<b>E</b>) consumed sucralose in their drinking water as in (<b>C</b>). They were subjected to the AOM-DSS protocol (injected with 10 mg/kg AOM on day 0 and given 3% DSS in the drinking water on days 7–14 and 28–35). Overall tumor number and composition of “large” tumors (>2 mm in any direction) are shown. Data are a composite of three (<b>C</b>) or two (<b>B</b> and <b>D</b>) independent experiments with five mice per group per experiment. Error bars represent the mean ± SEM. A two-way ANOVA (<b>C</b>) or Student <i>t</i> test (<b>D</b>) was used. *, <i>P</i> < 0.05; ns, not significant.</p>

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Damon Runyon Cancer Research Foundation (DRCRF)

Gateway Foundation (Gateway)

National Institutes of Health (NIH)

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ARTICLE ABSTRACT

Gut microbiota composition is directly associated with response to immunotherapies in cancer. The impact of diet on the gut microbiota and downstream immune responses to cancer remains unclear. In this study, we show that consumption of a common nonnutritive sweetener, sucralose, modifies microbiome composition, restricts T-cell metabolism and function, and limits immunotherapy response in preclinical models of cancer and patients with advanced cancer treated with anti–PD-1–based immune checkpoint inhibitors. Sucralose consumption is associated with a reduction in microbiota-accessible arginine, and amino acid supplementation or fecal microbiome transfer from anti–PD-1 responder mice completely restores T-cell function and immunotherapy response. Overall, sucralose consumption destabilizes the gut microbiota, resulting in compromised T-cell function and ablated immune checkpoint inhibitor response in cancer. This study highlights an unappreciated role of sucralose in reducing immunotherapy efficacy in both mouse models and samples from patients with cancer through shifts in the microbiome and arginine degradation that lead to T-cell exhaustion. T-cell function and immunotherapy responses are restored through amino acid supplementation.See related commentary by Chandra et al., p. 2196

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