Igniting Endogenous Calcipoptosis via ER‐Mitochondrial Calcium Shuttle Hijacking for Potent Antitumor Immunity

ABSTRACT The maintenance of intracellular calcium ion (Ca 2 + ) homeostasis plays a pivotal role in regulating both cellular survival and immunoregulatory pathways. However, achieving safe and precise manipulation of these messenger ions to engineer next‐generation antitumor immunotherapies remains a formidable challenge. Here, we reveal an organelle crosstalk paradigm that harnesses innate Ca 2+ dynamics to drive calcipoptosis‐mediated antitumor immunity, bypassing the limitations of conventional exogenous calcium‐dependent strategies. A modular peptide‐programmed nanoagonist was designed to activate self‐supplied calcium influx between Ca 2+ ‐rich and Ca 2+ ‐sensitive organelles by inducing endoplasmic reticulum stress and opening mitochondrial calcium transport channels under ultrasound irradiation. Moreover, the targeted dysfunction of dual‐organelles leads to the activation of the caspase‐dependent apoptotic pathway and the release of a cascade of damage‐associated molecular patterns to promote dendritic cell maturation and cytotoxic T‐cell infiltration. Additionally, Ca 2+ dysregulation polarizes macrophages into a pro‐inflammatory phenotype and stiffens cancer cells to establish biochemical and mechanical immunosurveillance. The nanoagonist demonstrated potent ablation of primary tumors and suppression of metastatic growth in breast and liver cancer models. Overall, this work enables customizable subcellular bioenergetic disruption without systemic toxicity risks, which pioneers a translatable strategy that redefines the frontier of calcium‐based immunotherapy.