Hydrogen Therapy Reverses Cancer‐Associated Fibroblasts Phenotypes and Remodels Stromal Microenvironment to Stimulate Systematic Anti‐Tumor Immunity

Abstract Tumor microenvironment (TME) plays an important role in the tumor progression. Among TME components, cancer‐associated fibroblasts (CAFs) show multiple tumor‐promoting effects and can induce tumor immune evasion and drug‐resistance. Regulating CAFs can be a potential strategy to augment systemic anti‐tumor immunity. Here, the study observes that hydrogen treatment can alleviate intracellular reactive oxygen species of CAFs and reshape CAFs’ tumor‐promoting and immune‐suppressive phenotypes. Accordingly, a controllable and TME‐responsive hydrogen therapy based on a CaCO 3 nanoparticles‐coated magnesium system (Mg‐CaCO 3 ) is developed. The hydrogen therapy by Mg‐CaCO 3 can not only directly kill tumor cells, but also inhibit pro‐tumor and immune suppressive factors in CAFs, and thus augment immune activities of CD4 + T cells. As implanted in situ, Mg‐CaCO 3 can significantly suppress tumor growth, turn the “cold” primary tumor into “hot”, and stimulate systematic anti‐tumor immunity, which is confirmed by the bilateral tumor transplantation models of “cold tumor” (4T1 cells) and “hot tumor” (MC38 cells). This hydrogen therapy system reverses immune suppressive phenotypes of CAFs, thus providing a systematic anti‐tumor immune stimulating strategy by remodeling tumor stromal microenvironment.