Carrier-free PANoptosis nanoinducers synergize with immunometabolic reprogramming for enhanced immunotherapy

Immunogenic cell death (ICD)-based immunotherapy holds great promise for cancer treatment, but the therapeutic effectiveness of ICD driven by a single death pathway is often limited due to tumor regulatory mechanisms and the immunosuppressive tumor microenvironment. To address these challenges, a carrier-free nanotherapeutic system (SN NPs) was developed by co-assembling an inducer of PANoptosis (a form of inflammatory programmed cell death that integrates pyroptosis, apoptosis, and necroptosis) with an indoleamine 2,3-dioxygenase 1 (IDO1) inhibitor to potentiate immunotherapy. By triggering mitochondrial dysfunction and excessive ROS generation, SN NPs induced a potent PANoptosis cascade, which markedly amplified ICD, facilitating dendritic cell maturation and subsequent antitumor immunity. Meanwhile, the co-delivered IDO1 inhibitor disrupted tryptophan metabolism-mediated immunosuppression, synergistically enhancing ICD-elicited immune activation and therapeutic efficacy. Comprehensive in vitro and in vivo studies demonstrated a favorable safety profile along with pronounced activation of antitumor immune responses and suppression of tumor growth. This work highlights the potential of PANoptosis induction coupled with immunometabolic reprogramming in enhancing immunotherapy.