Photoacoustic‐Imaging‐Guided Photothermal Regulation of Calcium Influx for Enhanced Immunogenic Cell Death

Abstract Immunogenic cell death (ICD) induced by calcium ion (Ca²⁺) overload has attracted significant attention owing to its ability to activate the immune system and generate durable antitumor immune responses. However, the slow release of Ca²⁺ by commonly used nanomodulators provides tumor cells with the opportunity to efficiently eliminate excess Ca²⁺ through ion channels, thus diminishing the therapeutic efficacy. Consequently, it is crucial to explore strategies for rapid Ca²⁺ release. To address this issue, a glutathione‐triggered Ca(IO₃)₂@starch‐based Ca²⁺ nanobomb is presented. This nanobomb not only enables accurate and efficient Ca²⁺ delivery to the tumor site but also exploits glutathione‐triggered photoacoustic (PA) imaging‐guided photothermal precise control of TRPV1 ion channel activation for enhancing the Ca²⁺ influx. Both in vitro and in vivo results confirm that the photothermally regulated Ca²⁺ influx based on this Ca²⁺ nanobomb effectively promotes ICD and stimulates immune infiltration in tumor tissues, ultimately leading to the effective inhibition of tumor growth and metastasis. The developed Ca²⁺ nanobomb presents a potential strategy to enhance ICD based on Ca²⁺ overload, thus addressing the challenges associated with precise and timely regulation of Ca²⁺ influx and offering prospects for improved antitumor immunotherapy.