Obesity is associated with profound immune dysregulation, driving chronic inflammation while compromising host defense against tumors. While trained immunity can enhance innate effector functions, it has thus far required parenteral administration of microbial ligands. Here, we show that incorporating a yeast-derived β-glucan supplement in mouse diets induces trained immunity via reprogramming of hematopoietic stem and progenitor cells. This dietary intervention leads to sustained production of metabolically enhanced monocytes and macrophages that rescue anti-tumor immunity in high-fat diet-induced obese mice, and corrects immune dysfunction sustained after weight loss. Our work reveals that yeast β-glucans act as functional “immuno-nutrients,” which remodel innate immunity and identifies the mucosal/bone-marrow axis as a target for dietary manipulations to restore immune resilience without impacting metabolism.

Keywords: CP: immunology; beta-glucan; dietary supplementation; hematopoiesis; immunometabolism; innate immunity; macrophage; monocyte; obesity; trained immunity; tumor immunity.

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