Synergistic Calcium Overload and Hydrogen Release Potentiate Robust Antitumor Immunity

ABSTRACT Immunogenic cell death (ICD) induced by calcium overload holds great promise for reversing the immunosuppressive tumor microenvironment (TME) and improving cancer immunotherapy. However, achieving sustained calcium dysregulation remains a major challenge. Herein, we report a novel nanoplatform, termed Ca@CMPN, which co‐delivers calcium hydride and curcumin using a mesoporous polydopamine carrier for synergistic ion‐interference and gas immunotherapy. Upon encountering the acidic TME, Ca@CMPN disintegrates to release Ca 2+ , initiating intracellular calcium overload, and concurrently generates hydrogen gas (H 2 ). Crucially, the co‐released curcumin acts from within the cell, amplifying the calcium overload by disrupting organellar calcium homeostasis, thereby ensuring robust ICD. Meanwhile, H 2 serves as a potent immunoadjuvant to alleviate oxidative stress and remodel the immunosuppressive TME. Both in vitro and in vivo studies demonstrate that Ca@CMPN effectively inhibits tumor growth and reprograms the TME, as evidenced by enhanced dendritic cell maturation, activation of cytotoxic T cells, and elevated levels of pro‐inflammatory cytokines (interferon‐γ (IFN‐γ) and tumor necrosis factor‐α (TNF‐α)). This work presents a paradigm‐shifting strategy that synergizes ion‐interference therapy with hydrogen immunotherapy, offering a powerful nanoplatform to unlock the full potential of cancer immunotherapy.