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Life sciences · Journal article
Cellular Oncology · September 25, 2026
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Immunoradiotherapy substantially improves the efficacy of non-small cell lung cancer (NSCLC) patients, but the response rate is only 40–60%. MHO7 (6-epi-ophiobolin G) from mangrove-derived fungus presents anti-tumor functions, and its derivative DM28 (C 32 H 48 O 4 ) potentially has more sustained activity. The present study aimed to systematically investigate the therapeutic potential and underlying mechanisms of DM28 on immunoradiotherapy efficacy in NSCLC. Lewis lung carcinoma mouse model were used to evaluate the anti-tumor effects of DM28 alone or combined with radiotherapy and anti-programmed cell death protein 1 therapy. Mechanistic studies included transcriptomic analysis, limited proteolysis-mass spectrometry, molecular docking, and dynamics simulations. Ferroptosis markers, damage-associated molecular patterns (DAMPs), and immune cell infiltration were assessed. DM28 modulated SLC3A2-associated ferroptosis by promoting the proteasomal degradation of SLC3A2 and inhibiting the SLC7A11/GPX4 axis, thereby suppressing tumor growth in NSCLC with a favorable safety profile. Furthermore, DM28 significantly enhanced NSCLC cell radiosensitivity accompanied by increased ferroptosis. The enhanced ferroptotic response promoted the release of DAMPs, including calreticulin and high mobility group box 1, thereby activating anti-tumor immune responses. Consequently, increased infiltration of activated CD8⁺ T cells were observed in the DM28-treated NSCLC tissues with immunoradiotherapy. DM28 potentiates immunoradiotherapy efficacy in NSCLC via inducing SLC3A2-dependent ferroptosis, which in turn enhances tumor immunogenicity. These findings provide a strong preclinical rationale for developing DM28 as a novel agent in combination strategies to improve therapeutic outcomes for NSCLC patients. Not applicable.