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.
Liang et al. (Sat,) studied this question.