Tumor Mechanical Remodeling via Bidirectional Calcium Redistribution Enables Deep Photothermal‐Immunotherapy

ABSTRACT Ca 2+ signaling serves as a core regulator controlling both cellular survival and immunomodulation pathways. Here, we report a paradigm‐shifting bidirectional Ca 2+ redistribution nanomodulator (RP@AA‐Lip) that rewires Ca 2+ homeostasis across intracellular‐extracellular compartments to orchestrate a self‐reinforcing mechanical‐immunological cascade for deep photothermal‐immunotherapy (PTI). This core‐shell nanomodulator RP@AA‐Lip consists of hypoxia‐targeting Rhodopseudomonas palustris (RP) as the photothermal core and an ascorbic acid (AA)‐enriched liposome (Lip) shell. Under NIR irradiation, RP activates TRPV1‐mediated Ca 2+ influx, while AA inhibits PMCA4‐driven Ca 2+ efflux, jointly triggering intracellular Ca 2+ overload to induce mitochondrial damage and thermoresistance reversal for amplified immunogenic cell death. We find that extracellular Ca 2+ depletion disassembles E‐cadherin junctions and softens tumor stiffness 4.23‐fold, enabling deep tumor penetration (up to 500 µm) and robust cytotoxic T cell (CTL) infiltration. Concurrently, the intracellular Ca 2+ overload further stiffens tumor cells to establish mechanical immunosurveillance that improves CTL‐mediated tumor killing. In triple‐negative breast cancer models, this integrated strategy elicits a robust antitumor immune cascade to remodel the tumor microenvironment and suppress tumor progression. Collectively, this work pioneers a compartmental Ca 2+ engineering strategy that unites nanomaterial design, ion signaling, and mechanical immunology, offering a transformative and translatable blueprint for deep PTI against stroma‐rich solid tumors.