Presenter(s)
M. Su, C. Wan, K. Yang, and Y. Sun; Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
Purpose/Objective(s): Disulfidptosis is driven by intracellular disulfide stress with actin-cytoskeleton collapse and has been linked to SLC7A11-dependent cystine uptake and limited pentose phosphate pathway (PPP)–derived NADPH. We tested whether radiotherapy under low-glucose conditions induces disulfidptosis by disrupting glucose metabolism and redox capacity in SLC7A11-high tumor cells, and assessed implications for radiosensitization and immunotherapy in vivo.
Materials/Methods: SLC7A11-high tumor cells were irradiated under low versus normal glucose. Cell-death modality was assessed by flow cytometry, immunofluorescence, and Western blotting with inhibitor profiling of major death programs and disulfidptosis-targeting interventions. Metabolomics and metabolic-flux analyses quantified glycolysis and PPP activity. In vivo, anti-angiogenic therapy was combined with radiotherapy in syngeneic subcutaneous lung carcinoma and melanoma models and a lung cancer patient-derived xenograft (PDX); anti–programmed cell death 1 (PD-1) therapy was evaluated in combination.
Results:
Under low-glucose conditions, radiotherapy markedly increased cell death in SLC7A11-high tumor cells. Pharmacologic inhibition of ferroptosis, apoptosis, autophagy, necroptosis, or pyroptosis failed to restore viability, whereas disulfidptosis-targeting interventions significantly attenuated cell death; Western blotting and immunofluorescence further supported a disulfidptosis-consistent phenotype. Metabolomic profiling revealed suppression of the pentose phosphate pathway (PPP) following radiotherapy under low glucose. Metabolic-flux analysis showed that radiotherapy increased glycolytic and PPP flux under normal glucose, while under low glucose these responses were blunted, with a more pronounced reduction in PPP flux. Consistently, SLC7A11 overexpression increased relative PPP flux under normal glucose, but this effect was abrogated under low glucose and further diminished after low-glucose radiotherapy. In vivo, combining radiotherapy with anti-angiogenic therapy significantly enhanced radiosensitivity in SLC7A11-high tumors across syngeneic subcutaneous models and a lung cancer patient-derived xenograft (PDX), and tumor tissues exhibited disulfidptosis-consistent molecular and morphologic features. Addition of anti–programmed cell death 1 (PD-1) therapy further improved antitumor efficacy, suggesting that disulfidptosis may contribute to immunotherapy potentiation.Conclusion:
With reduced glucose availability, radiotherapy limits PPP-derived NADPH supply, promotes disulfide stress, and triggers disulfidptosis in SLC7A11-high tumors, defining an actionable radiobiologic vulnerability. SLC7A11 may enable biomarker-guided radiosensitization using glucose-availability–lowering strategies, with potential added benefit from anti–PD-1 immunotherapy.