Mitochondrial metabolic reprogramming by a glutamine antagonist radioenhancer conjugate drives pyroptosis and antitumor immunity

Aberrant glutamine metabolism undermines the efficacy of cancer radiotherapy (RT) by promoting DNA repair, increasing oxygen consumption, and imposing metabolic stress that compromises the viability and function of cytotoxic T lymphocytes (CTLs). Here, we report a mitochondria-enriched, metabolism-regulating monolayered metal-organic framework (MOF) nanoplatform, Hf-Ir/DON, constructed by incorporating the glutamine antagonist 6-diazo-5-oxo-l-norleucine (DON) into a radiosensitizing hafnium-iridium (Hf-Ir) MOF to inhibit glutaminolysis. This design markedly sensitizes tumor cells to RT and, upon x-ray irradiation, enables mitochondria-targeted RT-radiodynamic therapy with substantially enhanced reactive oxygen species accumulation. The resulting oxidative stress induces extensive DNA damage, mitochondrial dysfunction, and immunogenic tumor cell pyroptosis. Concurrently, Hf-Ir/DON alleviates metabolic constraints on activated T cells, preserving CTL viability while sustaining effector and memory functions. In a murine colon cancer model, low-dose RT combined with Hf-Ir/DON achieved >95% tumor growth inhibition. Further combination with anti-PD-L1 therapy induced regression of bilateral triple-negative breast tumors and prevented lung metastasis. These results establish a radiometabolic MOF nanoplatform that potentiates RT while promoting durable antitumor immunity.