KEY POINTS
- This experimental preclinical study generated radioresistant B16 melanoma, MC38 colorectal, and A549 lung cancer cell lines using escalating irradiation to a cumulative dose of 50 Gy, followed by validation in immunocompetent mouse models.
- Radioresistant cells upregulated the ferroptosis-resistance genes SLC7A11 and FTH1 and showed reduced lipid peroxidation and intracellular ferrous iron after 15 Gy, consistent with impaired radiation-induced ferroptosis.
- A single 15 Gy dose inhibited parental B16 and MC38 tumors but had little effect on their radioresistant counterparts, which showed increased intratumoral regulatory T-cell accumulation.
- Irradiated radioresistant cells released more transforming growth factor beta 1 and promoted differentiation of naïve T cells into CD4-positive, CD25-positive, Foxp3-positive regulatory T cells.
- In B16 radioresistant tumors, sorafenib at 40 mg/kg once weekly for three doses combined with 15 Gy reduced tumor growth and regulatory T-cell infiltration compared with either treatment alone. Treatment toxicity was not systematically reported.
CLINICAL TAKEAWAY
The study proposes a mechanistic link between impaired radiation-induced ferroptosis, transforming growth factor beta 1 release, regulatory T-cell accumulation, and radioresistance. Pharmacologically promoting ferroptosis may improve radiotherapy response, but the evidence is limited to cell lines, mouse models, and exploratory human datasets and is not clinically actionable.