Dietary Fiber Lacks a Consistent Effect on Immune Checkpoint Blockade Efficacy Across Diverse Murine Tumor Models

Immune checkpoint blockade (ICB) has transformed cancer treatment, but success rates remain limited. Recent research suggests that dietary fiber enhances ICB efficacy through microbiome-dependent mechanisms. However, prior studies in mice compared grain-based chow (high fiber) with low–fiber-purified diet, but these diets also differed in other dimensions, including phytochemicals. Therefore, further work is needed to establish the robustness of the effect of fiber on ICB across cancer types and dietary contexts. In this study, we investigated gut microbiome composition, metabolite levels, and ICB activity in mice fed with grain-based chow or purified diets with differing quantities of isolated fibers (cellulose and inulin). Compared with dietary fiber content, consumption of chow versus purified diet had a greater effect on the gut microbiome and a much stronger impact on the metabolome. Studies in multiple tumor models revealed that fiber has a weaker impact on ICB (anti–PD-1) efficacy than previously reported. Although diet affected ICB in some models, the effect was not directionally consistent. None of the models tested displayed the pattern expected if fiber controlled ICB efficacy: strong efficacy in both chow and high–fiber-purified diet but low efficacy in low–fiber-prified diet. Thus, dietary fiber seems to have limited or inconsistent effects on ICB efficacy in mouse models, and other dietary factors that correlate with fiber intake may underlie clinical correlations between fiber consumption and immunotherapy efficacy. Significance: Clinical associations between high-fiber diets and improved immunotherapy efficacy may be driven by dietary factors correlated with fiber intake rather than fiber itself, which could impact dietary recommendations for patients undergoing immunotherapy.