Lung cancer is the most common type and the leading cause of cancer-related deaths worldwide . The most common type is non-small cell lung cancer (NSCLC) which comprises 80% of lung cancers . Selection of treatment for NSCLC mainly depends on the diagnostic stage of this disease and patient’s immune diversity. Basic treatments included surgical resection and radiotherapy (RT) that are often preferred and efficient for the patients with early-stage of NSCLC, whereas RT is used at least once in over 60% of lung cancer patients until cure or palliation of this disease . Moreover, sequential chemotherapy with RT or concurrent chemoradiotherapy is also suggested for disease remission in patients with locally advanced stage of lung cancer . It indicates that RT plays critical for NSCLC treatment, such as external beam radiation therapy and brachytherapy.
Personal medicine targeting specific gene characteristics currently applied in lung cancers, that results in better outcome for this disease . The main characteristic of NSCLC is EGFR overexpression: targeted therapies against EGFR such as tyrosine kinases inhibitors (TKIs), including the first-generation TKIs gefitinib and erlotinib, the second-generation TKI afatinib for EGFR and HER2 blockades, and the third-generation TKI osimertinib for EGFR T790M mutation have been demonstrated to improve clinical progression-free survival (PFS) compared with the conventional chemotherapies in patients with advanced NSCLC [17, 21]. For tumor recurrence and resistance to TKIs, other treatments such as platinum-based chemotherapy combined with an agent directed to either ALK rearrangements or ROS1 rearrangements are recommended for patients with metastatic stage of NSCLC [16, 51].
Besides, immunotherapy reactivating CD8+ T cells such as anti-PD-1 antibodies exhibits tumor therapeutic promise against NSCLC and results in 20% tumor remission in the patients fail to treatments of chemotherapies or targeted therapies [28, 52, 55]. To date, the monoclonal antibodies targeting PD-1 and PD-L1 interaction, pembrolizumab and nivolumab for PD-1 and atezolizumab for PD-L1, are approved by FDA for the treatment of metastatic NSCLC . The immune surveillance is responsible for outside infections and currently found to potentially eradicate tumors: CD8+ T cells recognize tumor cells and secrete ganzymen B (GZMB) and perforin (Prf1) to elicit tumor cell apoptosis and death . Immune checkpoints expressing in tumor cells, including PD-L1, galactine 9, HVEM, are able to exhaust CD8+ T cells and reduce CD8+ T-derived cytotoxicity [1, 43, 53]. In tumor microenvironment, IFNγ is secreted by T lymphocytes to reactivate macrophages and CD8+ T cells, but it also stimulates PD-L1 overexpression in tumor cells through JAKs-STAT1 signaling pathway . Meanwhile, EGFR-STAT3 axis also mediates PD-L1 expression in lung cancer . A case report has revealed a successful tumor therapy by Pembrolizumab immunotherapy in TKIs refractory NSCLC . But EGFR-resistance and downstream signaling gene STAT3 activated by other stimulations contribute to cell proliferation, anti-apoptosis, and resistance to CD8+ T cells in EGFR-positive lung cancer [46, 61].
Irradiation (IR) causes tumor DNA damage and results in consequent tumor apoptosis. In IR treatment, the accumulation of cytosolic DNA activates cGAS-STING signaling pathway , inducing type I IFN secretion and potentially reactivates immune surveillance against tumors. According to the preclinical and early clinical data, it demonstrates that IR enhances expression of MHC class I  and secretion of cytokines such as type I IFN , resulting in increase of homing rate of immune cells to tumor microenvironment [22, 41]. Therefore, IR-mediated tumor therapies are considered for improving anti-tumor efficacy of clinical immunotherapies [27, 37, 50]. In addition, type I IFN is able to induce PD-L1 expression that PD-L1 expression detection plays a critical role for anti-PD-1 therapies [2, 15]. Previous studies have demonstrated that low doses of fractionated IR significantly improves CD8+ T cell-mediated tumor remission in combination with anti-PD-1 or anti-PD-L1 therapies [15, 25, 26]. However, IFNγ from T lymphocytes and type I IFN from IR-treated tumors are able to activate JAKs-STAT1 axis [24, 49], that induces expressions of not only PD-L1 but also cell proliferation and anti-apoptosis genes [31, 54]. Since a previous study has indicated that UV light down-regulates IFNγ-mediated STAT1 phosphorylation , we, therefore, proposed a hypothesis that IR may augment CD8+ T cells-mediated cytotoxicity through blocking IFNs-mediated activations of JAKs-STATs to against immunotherapies-resistant EGFR-positive NSCLC.