Calcium ion nanomodulators induce pyroptosis for tumor immunotherapy

Pyroptosis is a promising strategy for tumor immunotherapy, but nanomaterial-based pyroptosis inducers remain underexplored. Here, we developed a pH-responsive calcium nanomodulator by loading curcumin onto ultrathin Ca/Al layered double hydroxide nanosheets (LDH-CUR). LDH-CUR induces pyroptosis <i>via</i> mitochondrial calcium overload. Upon internalization by tumor cells, it degrades in acidic environments, releasing calcium ions while curcumin blocks calcium efflux, leading to calcium surges. This triggers reactive oxygen species production, cytochrome C release, and caspase-3 activation. Caspase-3 cleaves gasdermin E (GSDME), forming transmembrane pores and inducing pyroptosis. Pyroptosis releases inflammatory molecules, activating robust adaptive immunity to target primary tumors and suppress metastases. LDH-CUR demonstrates a novel approach to combining pyroptosis induction with immunotherapy, offering potential for nanomaterial-based cancer treatments.