A novel pH-responsive nanoreactor for pyroptosis induction: multifaceted ROS amplification drives potent immunotherapy against triple-negative breast cancer

Triple-negative breast cancer (TNBC) is associated with rapid progression and poor sensitivity to monotherapies, necessitating combination strategies to enhance tumor immunogenicity, reprogram the tumor microenvironment (TME), and convert immunologically “cold” tumors into “hot” ones. In this study, we develop a pH-responsive, pyroptosis-inducing nanoreactor, ZnS/ZIF-90:Fe/Vk3 (ZZFV), designed to elicit potent antitumor immunity. Under acidic conditions, ZZFV rapidly degrades, releasing Zn 2+ , Fe 2+ , H 2 S, and Vk3. H 2 S promotes glucose uptake and consumption while downregulating cytochrome c oxidase subunit IV (COX IV) expression, whereas Zn 2+ suppresses lactate dehydrogenase (LDH) activity, collectively disrupting glucose metabolism and exacerbating intracellular acidification. Meanwhile, NAD(P)H quinone oxidoreductase 1 (NQO1), highly expressed in tumor cells, catalyzes the conversion of Vk3 to H 2 O 2 , which is subsequently converted to highly toxic •OH through Fe 2+ -mediated Fenton reactions. Additionally, Zn 2+ and H 2 S synergistically disrupt mitochondrial function, thereby amplifying reactive oxygen species (ROS) production. Excessive ROS triggers Caspase-1–dependent pyroptosis, leading to the liberation of damage-associated molecular patterns. These events promote dendritic cell (DC) maturation, robust T-cell activation, M1 macrophage polarization, and expansion of central memory T-cell populations, thereby conferring durable immune protection. Consequently, ZZFV demonstrates potent antitumor efficacy, effectively overcoming immune tolerance in TNBC and achieving robust, sustained antitumor immunity.