ABSTRACT: Lung cancer (LC) is one of the most frequently diagnosed cancers and the leading cause of cancer death worldwide, and most LCs are non-small cell lung cancer (NSCLC). Radiotherapy is one of the most effective treatments for patients with lung cancer, either alone or in combination with other treatment methods. However, radiotherapy responses vary considerably among NSCLC patients. The efficacy of radiotherapy is influenced by several factors, among which autophagy is of importance. Autophagy is induced by radiotherapy and also influences cell responses to radiation. We explored the clinical significance of autophagy-related genes (ARGs) and gene sets (ARGSs) and the underlying mechanism in NSCLC patients treated with radiotherapy. First, differentially expressed ARGs (SNCA, SESN3, DAPL1, and ELAPOR1) and miRNAs (miR-205-5p, miR-26a-1-3p, miR-6510-3p, miR-194-3p, miR-215-5p, and miR-375-3p) were identified between radiotherapy-resistant and radiotherapy-sensitive groups. An autophagy-related radiosensitivity risk signature (ARRS) by nine ARmRNAs/miRNAs and an autophagy-related overall survival risk signature (AROS) by three ARmRNAs were then constructed with estimated AUCs of 0.8854 (95% CI: 0.8131-0.9576) and 0.7901 (95% CI: 0.7168-0.8685), respectively. The correlations between ARGSs or prognostic signatures and clinicopathological factors, short-term radiotherapy responses (radiotherapy sensitivity), long-term radiotherapy responses (overall survival), and immune characteristics were analyzed. Both ARGSs and prognostic signatures were related to immune checkpoint inhibitors (ICIs), infiltration of tumor-infiltrating immune cells (TIICs), and the activity of the cancer immune cycle. Finally, after target prediction and correlation analysis, circRNA (hsa_circ_0019709, hsa_circ_0081983, hsa_circ_0112354, hsa_circ_0040569, hsa_circ_0135500, and hsa_circ_0098966)-regulated miRNA/ARmRNA axes (miR-194-3p/SESN3, miR-205-5p/ELAPOR1, and miR-26a-1-3p/SNCA) were considered potential modulatory mechanisms by influencing the regulation of autophagy, macroautophagy, and chaperone-mediated autophagy.
