Optimizing the timing of JAK1 inhibition preserves the anti-tumor efficacy of radioimmunotherapy in lung cancer by preventing T cell exhaustion.

JAK1 inhibitors are widely used in hematologic malignancies and autoimmune diseases, their potential in combination with immunotherapy for solid tumors such as lung cancer is increasingly being recognized. The combination of radiotherapy and immunotherapy (radioimmunotherapy, iRT) has become a standard treatment strategy for lung cancer, but the impact of JAK1 inhibitors on the antitumor efficacy of iRT remains insufficiently explored. This study aimed to investigate the anti-tumor effects of JAK1 inhibition on iRT and the underlying mechanisms. The direct effects of JAK1 inhibitor on lung cancer were evaluated in vitro using cell proliferation, colony formation, and wound healing assays, and in vivo using immunodeficient mouse models. In addition, in immunocompetent mouse models of subcutaneous and orthotopic lung tumors, we analyzed the influence of JAK1 inhibitor on the tumor immune microenvironment during iRT, with a focus on the T-cell function. The results revealed that although JAK1 inhibitor monotherapy markedly suppressed lung tumor growth, its concurrent administration unexpectedly compromised the antitumor efficacy of iRT, an effect associated with impaired CD8⁺ T cell activity and interferon-γ (IFN-γ) production. In contrast, short-term delayed administration of the JAK1 inhibitor approximately one week after completing iRT was found to mitigate T-cell exhaustion, optimize immune responses, and thereby preserve the antitumor efficacy of iRT. In conclusion, concurrent use of JAK1 inhibitor during iRT should be avoided in lung cancer treatment. Optimizing the timing of JAK1 inhibition represents a promising strategy to mitigate immunosuppression while maintaining therapeutic efficacy.