Sweet boost: Sucralose enhances regulatory T cell (Treg) functions in vitro

Non-nutritive sweeteners (NNS) like sucralose, aspartame, and saccharin are widely used as sugar alternatives. While the FDA considers NNS safe, concerns about their long-term effects are growing. Sucralose, derived from sucrose and about 600 times sweeter, has been shown to dampen the efficacy of anti PD-1 in cancer in both mice and human. It lowers the T- cell cytotoxic function and enhances regulatory T cell (Treg) proliferation. Tregs are vital for immune tolerance but potently suppress anti-tumor immunity in the tumor microenvironment. How sucralose enhances Treg function still unknown, representing a critical gap in understanding potential dietary influences on cancer immunotherapy. Therefore, studying the sucralose -Tregs interactions is a novel approach to understand possible resistance mechanisms in cancer. We isolated Tregs from Foxp3-reporter mice and treated them with varying concentrations of sucralose in vitro . Cell proliferation was monitored daily via cell counting, while Tregs phenotype and function were evaluated using flow cytometry. A suppression assay was performed by coculturing Tregs (treated with 0 mM, 0.05 mM, or 0.5 mM sucralose) with CD8+ T cells. Sucralose's effect on Treg differentiation and metabolism was assessed using the naïve CD4+ T cell differentiation and Seahorse assays, respectively. Our study showed that sucralose significantly enhances proliferation, suppressive capacity, and differentiation of Treg in vitro while also increasing the mitochondrial spare respiratory capacity, suggesting improved metabolic fitness in these cells. These findings highlight the interactions between sucralose and Tregs, which may help us to understand how artificial sweeteners influence immune regulation and resistance mechanisms in cancer, offering insights for future in vivo research and informing dietary recommendations and immune modulation strategies in cancer treatment.