Dietary Commensal Wrestles Iron from Tumor Microenvironment to Activate Antitumoral Macrophages

The microbiome dictates the response to cancer immunotherapy efficacy. However, the mechanisms of how the microbiota impacts therapy efficacy remain poorly understood. In a recent issue of Nature Immunology, Sharma and colleagues elucidate a multifaceted, macrophage-driven mechanism exerted by a specific strain of fermented food commensal plantarum strain IMB19, LpIMB19. LpIMB19 activates tumor macrophages, resulting in the enhancement of cytotoxic cluster differentiation 8 (CD8) T cells. LpIMB19 administration led to an expansion of tumor-infiltrating CD8 T cells and improved the efficacy of anti-PD-L1 therapy. Rhamnose-rich heteropolysaccharide, a strain-specific cell wall component, was identified as the primary effector molecule of LplMB19. Toll-like receptor 2 signaling and the ability of macrophages to sequester iron were both critical for rhamnose-rich heteropolysaccharide-mediated macrophage activation upstream of the CD8 T-cell effector response and contributed to tumor cell apoptosis through iron deprivation. These findings reveal a well-defined mechanism connecting diet and health outcomes, suggesting that diet-derived commensals may warrant further investigation. Additionally, this work emphasizes the importance of strain-specific differences in studying microbiome-cancer interactions and the concept of "nutritional immunity" to enhance microbe-triggered antitumor immunity.