Applications of circulating tumor DNA in unresectable and advanced non-small cell lung cancer immunotherapy: from stratification to therapeutic guidance.

Non-small cell lung cancer (NSCLC) remains one of the leading causes of cancer-related mortality worldwide. Although immune checkpoint inhibitors (ICIs) have significantly improved outcomes in patients with unresectable stage III and advanced disease, the lack of robust predictive biomarkers continues to limit patient selection and treatment optimization. Circulating tumor DNA (ctDNA) has emerged as a minimally invasive and dynamic biomarker that enables comprehensive tumor profiling. In this review, we summarize recent advances in ctDNA detection technologies, including quantitative PCR, digital PCR, and next-generation sequencing approaches, and discuss their clinical applications in immunotherapy. We highlight the role of ctDNA in pre-treatment stratification to identify patients most likely to benefit, as well as its utility in real-time monitoring of therapeutic response and disease progression. Furthermore, we discuss emerging high-sensitivity techniques and multi-omics integration strategies that may further enhance the precision of ctDNA-based analysis. Overall, ctDNA holds significant potential to refine clinical decision-making and advance personalized immunotherapy in unresectable and advanced NSCLC.