Ferrous fluoride nanoinitiators reprogram tumor stemness to empower ultrasound-augmented pyroptosis for potent catalytic immunotherapy

Pyroptosis, a pro-inflammatory programmed cell death mechanism, plays a pivotal role in immune activation. While ultrasound (US)-enhanced catalytic therapy can trigger pyroptosis through increased oxidative stress, tumor cells frequently circumvent this process via intrinsic resistance mechanisms. Herein, ferrous fluoride (FeF2) nanoinitiators were developed to promote US-enhanced catalytic activity via stemness reprogramming to amplify pyroptosis-driven antitumor immunity. The incorporation of F significantly reduced the energy barrier during FeF2-mediated H2O2 catalysis, thereby boosting ROS generation. US irradiation further potentiated this catalytic process, leading to rapid ROS accumulation. Notably, F was found to suppress Wnt/β-catenin signaling in cancer cells by upregulating the endogenous inhibitor DKK1. This stemness attenuation mechanism enhanced tumor cell susceptibility to oxidative stress, consequently promoting pyroptosis. The resulting immunogenic cascade triggered dendritic cell (DC) maturation and increased cytotoxic T-cell infiltration, effectively overcoming immunosuppression and suppressing tumor growth. In bilateral tumor models, synergistic effects with immune checkpoint blockade (ICB) therapy elicited robust systemic immune responses, significantly enhancing therapeutic outcomes. This innovative approach bridges the therapeutic gap through synchronized stemness reprogramming and pyroptosis induction, establishing a paradigm for precision-engineered nanoinitiators in advanced catalytic immunotherapy.