Covalent Organic Frameworks‐Delivered Reuterin Drives Trained Immunity in Tumor‐Associated Macrophages to Enhance Melanoma Immunotherapy via Glycerophospholipid Metabolism

Abstract The gut microbiota is increasingly recognized as a promising therapeutic target in cancer treatment. However, the specific mechanisms by which gut bacteria and their metabolites exert therapeutic effects in melanoma remain poorly understood. In this study, it is unexpectedly demonstrated that prophylactic supplementation with Limosilactobacillus reuteri exhibits significant tumor‐suppressive properties, primarily mediated by its secreted metabolite, reuterin. This metabolite induces trained immunity through macrophage metabolic reprogramming, thereby enhancing antitumor immune responses. Mechanistically, this process involves stabilizing HIF‐1α via the AHR‐ROS signaling pathway, enhancing glycerophospholipid metabolism, and elevating arachidonic acid levels, thereby amplifying the trained immunity response. Similar to reuterin, arachidonic acid also induces trained immunity and facilitates macrophage‐mediated tumor cell killing. To enhance its therapeutic efficacy, reuterin is encapsulated in covalent organic frameworks (COFs). COF‐Reuterin demonstrates superior effects in tumor‐associated macrophages (TAMs), remodulating intratumor bacteria and directly facilitating tumor cell killing. Notably, COF‐Reuterin demonstrates superior therapeutic efficacy compared to cisplatin. Furthermore, COF‐Reuterin reprogrammed TAMs from an M2 to an M1 phenotype, increasing CD8 + T cell infiltration and decreasing myeloid‐derived suppressor cells (MDSCs), reshaping the immunosuppressive tumor microenvironment. These findings highlight the potential of probiotics and their metabolites in the metabolic reprogramming of TAMs, offering a promising cancer therapeutic approach.