Photosensitive calcium-based nanoinducer for NIR-triggered immunogenic cell death and anti-tumor immunity

Immunogenic cell death (ICD) is a unique form of apoptosis that enables immunocompetent hosts to elicit specific immune responses against antigens associated with dying cells. Pyroptosis, a recently identified lytic programmed cell death pathway, can be utilized to achieve ICD. However, most pyroptosis inducers are inflammatory small molecules or chemical activators, which are often limited by drug resistance and systemic toxicity. Here, we present a photosensitive calcium-based nanoinducer (CaNMs@SP) that modulates intracellular calcium levels to enhance ICD effectiveness, providing a strategy to improve cancer immunotherapy by directly regulating calcium signaling. Under 750 nm light irradiation, CaNMs@SP can promote the influx of exogenous calcium ions into tumor cells through photothermal therapy (PTT) and photodynamic therapy (PDT), while the calcium ions carried by the nanomaterials diffuse within the tumor cells, resulting in an accumulation of calcium ions inside the tumor cells. This induces calcium ions overload, causing tumor cell swelling, membrane rupture, leading to ICD and the emission of damage-associated molecular patterns (DAMPs), thereby activating the anti-tumor immunity. In vitro studies confirm the upregulation of Caspase-3 and GSDME that induce tumour swelling and cell death induction. In vivo experiments show tumor ablation, T cell activation, and tumor recurrence inhibition, highlighting the potential of CaNMs@SP as a personalized immunotherapy through pyroptosis-dependent ICD. STATEMENT OF SIGNIFICANCE: We developed a photosensitive calcium-based nanoinducer (CaNMs@SP) that triggers calcium overload to induce pyroptosis-dependent immunogenic cell death (ICD). Unlike conventional small-molecule inducers, this platform avoids drug resistance and systemic toxicity by integrating photothermal/photodynamic therapy with calcium ion modulation. Demonstrating effective tumor ablation, T cell activation, and recurrence inhibition, CaNMs@SP offers a promising strategy for personalized cancer immunotherapy.