Mitochondrial metabolic reprogramming by a glutamine antagonist radioenhancer conjugate drives pyroptosis and antitumor immunity
- 1Department of Chemistry, University of Chicago, 929 East 57th Street, Chicago, IL 60637, USA.
- 2Department of Radiation and Cellular Oncology and Ludwig Center for Metastasis Research, University of Chicago, 5758 South Maryland Avenue, Chicago, IL 60637, USA.
- 3Department of Chemistry, Westlake University, 600 Dunyu Road, Hangzhou 310030, Zhejiang, China.
Abstract
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.
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BibTeX
@article{song2026mitochondrial,
title = {{Mitochondrial metabolic reprogramming by a glutamine antagonist radioenhancer conjugate drives pyroptosis and antitumor immunity}},
author = {Rundi Song and Jinhong Li and Chaoyu Wang and Langston Tillman and Yibin Mao and Yuxuan Xiong and Xuan Li and Ralph R. Weichselbaum and Wenbin Lin},
journal = {Science Advances},
year = {2026},
month = oct,
doi = {10.1126/sciadv.aeh5903},
url = {https://www.science.org/doi/abs/10.1126/sciadv.aeh5903},
note = {CC BY-NC},
}
RIS
TY - JOUR
TI - Mitochondrial metabolic reprogramming by a glutamine antagonist radioenhancer conjugate drives pyroptosis and antitumor immunity
AU - Rundi Song
AU - Jinhong Li
AU - Chaoyu Wang
AU - Langston Tillman
AU - Yibin Mao
AU - Yuxuan Xiong
AU - Xuan Li
AU - Ralph R. Weichselbaum
AU - Wenbin Lin
PY - 2026
DA - 2026/10/30
JO - Science Advances
DO - 10.1126/sciadv.aeh5903
UR - https://www.science.org/doi/abs/10.1126/sciadv.aeh5903
AB - 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.
SN - 2375-2548
ER -