Thyroxine alleviates interstitial lung disease induced by combined radiotherapy and immunotherapy

Immune checkpoint blockade (ICB) combined with radiotherapy (RT) has improved patients survival, but also increased the risk of pulmonary adverse effects (AEs). Therefore, to explore potential drug targets for interstitial lung disease (ILD). We investigated the interaction of ICB and RT in pulmonary AEs using the disproportionality analysis and COX regression. Genome-wide association studies, transcriptome analysis, and vivo models highlighted the role of programmed death-ligand-1 (PD-L1) in ILD. Mendelian randomization analysis identified drug targets. Clinical data on pulmonary AEs in patients with non-small cell lung cancer (NSCLC) were used to validate the finding. Herein, we confirmed ICB combined with RT posed the highest risk of pulmonary AEs, with reporting odds ratio of interaction effect was 3.727. Anti-PD-L1 posed a greater risk of pulmonary AEs compared to anti-PD-1 (Hazard Ratio = 9.355) or anti-cytotoxic lymphocyte antigen-4 (CTLA-4) (Hazard Ratio = 6.985). In vivo study, PD-L1 expression in radiation induced lung injury negatively correlated with collagen deposition. Notably, thyroid hormone receptors were identified as drug targets for ILD. Our results demonstrate that thyroxine exerts a significant inhibitory effect on pulmonary fibrosis progression. Clinical evidence robustly supports the correlation between thyroid function and ILD. These findings highlight the importance of PD-L1 and thyroxine in understanding and managing ILD.