A Programmable Calcification Nanoplatform for Loco‐Regional Calcification‐Immune Hepatocellular Carcinoma Therapy

ABSTRACT Inducing tumor calcification is a promising strategy for disrupting cancer progression, yet achieving efficient biomineralization with synergistic antitumor effects remains challenging. Here, a programmable calcification nanoplatform (CaIM) is developed using in situ growth of calcium peroxide (CaO ₂ ) on black phosphorus (BP) nanosheets, followed by hyaluronic acid encapsulation. Unlike conventional physical adsorption or co‐precipitation, this in situ growth strategy yields crystalline CaO ₂ uniformly anchored on the BP matrix, enabling synchronized release of Ca ^{2 +} , phosphate, and H ₂ O ₂ in the tumor microenvironment. CaIM induces potent intracellular calcium overload and oxidative stress, triggering mitochondrial dysfunction, cell death, and extensive biological calcification readily visualized via computed tomography (CT). Multi‐omics profiling identifies the mucolipin channel MCOLN2 as a key mediator regulating calcium flux, facilitating stable active biomineralization rather than passive necrotic calcification. This active calcification, coupled with mitochondrial damage, effectively reshapes the immunosuppressive microenvironment by promoting macrophage polarization and T cell infiltration. These findings establish a calcium signaling‐driven paradigm integrating nanocomposite design with synergistic calcium stress, oxidative damage, and immune activation, offering a robust foundation for calcification‐based cancer therapy.