Prognostic Value Of Nucleic Acid Sensing-Related Genes In Lung Cancer And The Role Of IFI16 In Radiation-Related Immunotherapeutic Effects

In recent years,more and more studies have highlighted the importance of nucleic acid sensing pathways in cancer research.The primary role of nucleic acid sensing pathways is to recognize heterologous nucleic acids and trigger immune responses.During the development of tumors,nucleic acid sensing pathways can recognize heterologous nucleic acids released by cell mutations and necrosis,thus triggering immune response pathways and affecting tumor progression and immune evasion.Nucleic acid sensing pathways can also identify nucleic acid fragments released during tumor treatments.For instance,following radiotherapy and chemotherapy,which damage tumor cell DNA,unrepaired nucleic acids enter the cytoplasm as micronuclei and are recognized by nucleic acid sensors.The result leads to the activation of downstream immune pathways and releases immune-related factors such as cytokines and chemokines.Considering the importance of nucleic acid sensing pathways in tumors,nucleic acid sensing genes may have great potential in tumor classification,treatment response prediction,prognosis assessment,and development of new treatment targets.However,research in this field is still limited at present.Therefore,this study aims to explore the application value of nucleic acid sensing pathways in non-small cell lung cancer(NSCLC),including constructing an NSCLC prognosis prediction model based on nucleic acid sensing pathways,screening potential therapeutic target genes,providing new theoretical basis and potential treatment targets for radiotherapy-related immune effects.This study employs bioinformatics methods based on large-sample NSCLC transcriptomic data from public databases to investigate the predictive value of nucleic acid sensing-related genes for the long-term survival and treatment response of NSCLC patients.This study identifies the presence of nucleic acid sensing-activated and-suppressed subtypes in NSCLC,with patients of the activated subtype showing better prognosis and immune therapy response.This study subsequently developed a riskscoring model based on nucleic acid sensing genes to classify patients into high-risk and low-risk groups,corresponding to the suppressed and activated subtypes of nucleic acid sensing.After validation by various scoring systems and independent databases(GSE31210,GSE37745,GSE8894,GSE50081,GSE126044,IMvigor210),the model proved to be effective in forecasting the prognosis of NSCLC patients and recognizing individuals who would benefit from immunotherapy and radiotherapy.The study also found that the low-risk patient group(those with the nucleic acid sensing-activated subtype)was more likely to benefit from radiotherapy.This result suggests that high expression of specific nucleic acid sensing genes may enhance the efficacy of radiotherapy in treating NSCLC.To identify core nucleic acid sensing genes that affect the efficacy of radiotherapy,we combined bioinformatics analysis and cellular experiments to screen the core nucleic acid sensing genes intimately associated with NSCLC prognosis and the immune microenvironment.Results revealed that Interferoninducible protein 16(IFI16)shows a significant correlation with NSCLC prognosis and immune checkpoints and is notably upregulated during radiotherapy-induced immune responses.Further experiments demonstrate that IFI16 significantly affects macrophage polarization and lymphocyte infiltration within tumors post-radiotherapy,substantially impacting the efficacy of radiotherapy alone and in combination with immunotherapy.In terms of mechanism,On one hand,IFI16 activates the STING-IRF3-IFN-I pathway by recognizing radiotherapy-induced double-strand DNA breaks.On the other hand,IFI16 inhibits DNA repair proteins like γ-H2 AX,ATM,ATR,DNA-PK,and MRN,enhancing cytoplasmic DNA accumulation and consequently positively feeding back into the activation of IFI16 and downstream nucleic acid sensing and immune pathways.In summary,nucleic acid sensing genes and pathways play a significant role in predicting the long-term prognosis of NSCLC and the effectiveness of radiotherapy and immunotherapy.The core molecule IFI16 mediates radiotherapy-related immune effects by recognizing double-stranded DNA breaks post-radiotherapy,inhibiting DNA repair and enhancing DNA release.These results suggest that IFI16 may serve as a molecular target for enhancing the immune effects of radiotherapy.