Catalytic immunotherapy via ultrasmall Ir supported metal clusters on defect-engineered nanoplatforms for tumor metabolic disruption and enhanced immunogenic cell death

Immunogenic cell death (ICD) is a promising immunotherapy route, yet its efficacy is hampered by modest ICD induction and the hostile tumor microenvironment (TME). We engineer a multifunctional nanocatalyst (G@Ir/MnFe-MMO), with tailored MnFe-MMO nanosheets containing abundant oxygen vacancies (O_v) that serve as anchoring sites for ultrasmall Ir-supported metal clusters (Ir-SMCs) and form Mn–O_v–Fe electron bridges to facilitate directional electron transfer. This unique structural arrangement enhances catalytic activity by accelerating ROS generation at Ir-SMCs sites and enabling efficient NADH (reduced nicotinamide adenine dinucleotide) oxidation, thereby inducing redox disequilibrium and collapsing tumor metabolic homeostasis. Upon 808 nm laser irradiation, oxidative stress and the rapid NADH depletion collapses redox balance, depolarizes the mitochondrial membrane and drains adenosine triphosphate (ATP), provoking sustained endoplasmic reticulum (ER) stress that magnifies damage-associated molecular patterns (DAMPs) release and strengthens ICD. Furthermore, the loaded lactate dehydrogenase A (LDHA) inhibitor GNE-140 quenches lactate production and blocks NAD⁺ (oxidized nicotinamide adenine dinucleotide) regeneration, ultimately relieving TME-driven immunosuppression and enhancing the persistence and activity of inflammatory immune cells within TME. Consequently, G@Ir/MnFe-MMO not only induces potent ICD but also enhances tumor immune infiltration and systemic antitumor responses, leading to significant suppression of both primary and distant tumors in vivo. This strategy provides a compelling therapeutic paradigm for overcoming tumor metabolic plasticity and boosting the clinical efficacy of ICD-based tumor immunotherapy.