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

Ca²⁺ signaling serves as a core regulator controlling both cellular survival and immunomodulation pathways. Here, we report a paradigm-shifting bidirectional Ca²⁺ redistribution nanomodulator (RP@AA-Lip) that rewires Ca²⁺ 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 Ca²⁺ influx, while AA inhibits PMCA4-driven Ca²⁺ efflux, jointly triggering intracellular Ca²⁺ overload to induce mitochondrial damage and thermoresistance reversal for amplified immunogenic cell death. We find that extracellular Ca²⁺ 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 Ca²⁺ 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 Ca²⁺ 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.