Heteroleptic ruthenium(II) complexes-based sonocatalysts trigger gasdermin D palmitoylation to augment hypoxia-resistant non-canonical pyroptotic immunotherapy.

Sonodynamic therapy is expected to induce pyroptosis of cancer cells and activate the immune response. However, its efficacy is limited by the tumor hypoxic microenvironment. Moreover, these sonosensitizers trigger a gasdermin D palmitoylation-associated non-canonical pyroptosis pathway to boost tumor immunogenicity, there is a lack of research. Herein, a series of heteroleptic Ru(II) polypyridine-single-layered g-C3N4 QDs conjugates is developed. Among them, Ru1SLCN with phen and dppz ligands, as a sonocatalyst, catalyzed the decomposition of H2O or H2O2 to excessively accumulate reactive oxygen species in mitochondria through ultrasonically driven electron-hole pair separation and band tilting. Ru1SLCN can disrupt mitochondrial oxidative metabolism while upregulating the expression of ZDHHC5 and ZDHHC9 proteins to promote palmitoylation of GSDMD and GSDMD-NT. Meanwhile, Ru1SLCN induced mitophagy inhibition, disrupting the pyroptosis checkpoint and ultimately enhancing the efficacy of non-canonical pyroptosis. This triggers extensive membrane perforations, leading to the release of cellular content and damage-associated molecular patterns, which further potentiate long-term immune responses. This is accompanied by the effective reshaping of the immunosuppressive microenvironment, thereby significantly inhibiting tumor growth and metastasis. Our work introduces, for the first time, a novel approach to sono-immunotherapy by activating GSDMD palmitoylation-mediated non-canonical pyroptosis, thereby offering an additional target for modulating immune activity in metalloimmunotherapies.