Disrupting tumor homeostasis with an autoamplificatory nanoinducer to augment pyroptosis for efficient immunotherapy.

Abnormal tumor homeostasis is crucial in maintaining tumor cell survival and growth. Thus, developing effective antitumor strategies that can simultaneously disrupt multiple intracellular homeostatic mechanisms may be more effective and less laborious. Herein, an autoamplificatory nanoinducer (CLRN) composed of photosensitizer Ce6, glucose metabolism inhibitor lonidamine and methyltransferase inhibitor RG108 is designed and constructed to enhance pyroptosis and upregulate immunosurveillance by disrupting intracellular redox and metabolic homeostasis. CLRN reduces oxygen consumption by disrupting glucose metabolic homeostasis in hypoxic environments, leading to a massive generation of reactive oxygen species that further disrupt intracellular redox homeostasis. Additionally, CLRN inhibits DNA methylation to upregulate gasdermin E (GSDME) expression, which cooperates with the amplified oxidative stress to activate the Caspase-3/GSDME pathway and activate immunogenic pyroptosis. As tumor cells undergo immunogenic pyroptosis, they release various damage-associated molecular patterns and pro-inflammatory cytokines, which promote immune cell infiltration. Furthermore, CLRN reduces lactic acid production by disrupting glucose metabolic homeostasis, thereby reversing the immunosuppressive tumor microenvironment and synergistically eliciting a robust immune response. Ultimately, the developed autoamplificatory nanoinducer effectively suppresses the growth of primary and distant tumors. This facile and feasible design of versatile carrier-free nanoinducer provides an effective approach to trigger immunogenic pyroptosis and enhance antitumor immunotherapy.