Disulfiram alone regulates the radiosensitivity of lung cancer through NF-κB pathway and regulates the immune microenvironment after radiotherapy by targeting PD-L1 through c-Myc

Background

Lung cancer often develops resistance to radiotherapy (RT), which undermines its therapeutic efficacy. Disulfiram (DSF), a drug commonly used in the treatment of alcohol use disorders, has shown potential in inducing anti-tumor effects. However, its impact on radioresistance in lung cancer and its effects on the tumor immune microenvironment have not been fully elucidated.

Methods

Clonogenic assays, Rad51 foci formation, and a nude mouse model were employed to assess the impact of DSF on lung cancer radiosensitivity. Immune profiling was conducted using flow cytometry, and downstream mechanisms were investigated using RT-qPCR and Western blotting. The therapeutic effects of the combination of DSF, RT, and anti-PD-L1 antibody were further validated in a C57BL/6 mouse tumor model.

Results

DSF increased radiosensitivity in lung cancer cells, enhanced CD8⁺ T cell infiltration, and upregulated PD-L1 expression through c-Myc. The combination of DSF, RT, and anti-PD-L1 antibody resulted in the most significant anti-tumor effects.

Conclusions

DSF effectively mitigates radioresistance in lung cancer and enhances the efficacy of radioimmunotherapy, offering a promising therapeutic strategy for improving treatment outcomes.