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

In a murine colon cancer model, low-dose radiotherapy combined with the mitochondria-targeted Hf-Ir/DON nanoplatform achieves >95% tumor growth inhibition.

• Why it matters: Aberrant glutamine metabolism can blunt radiotherapy by boosting DNA repair, oxygen consumption, and metabolic stress that impairs cytotoxic T lymphocytes.
• What they did: The study builds a mitochondria-enriched Hf-Ir MOF incorporating the glutamine antagonist DON to inhibit glutaminolysis, then uses x-ray irradiation to drive RT-radiodynamic reactive oxygen species production.
• The result: Oxidative stress from Hf-Ir/DON triggers DNA damage, mitochondrial dysfunction, and immunogenic pyroptosis while preserving CTL viability and effector/memory functions, and anti-PD-L1 plus Hf-Ir/DON with RT regresses bilateral triple-negative breast tumors and prevents lung metastasis.

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