Current advances and future prospects of blood-based techniques for identifying benign and malignant pulmonary nodules

Lung cancer is the leading cause of cancer-related mortality worldwide, highlighting the urgent need for more accurate and minimally invasive diagnostic tools to improve early detection and patient outcomes. While low-dose computed tomography (LDCT) is effective for screening in high-risk individuals, its high false-positive rate necessitates more precise diagnostic strategies. Liquid biopsy, particularly ctDNA methylation analysis, represents a promising alternative for non-invasive classification of indeterminate pulmonary nodules (IPNs). This review highlights the progress and clinical potential of liquid biopsy technologies, including traditional proteins markers, cfDNA, exosomes, metabolomics, circulating tumor cells (CTCs) and platelets, in lung cancer diagnosis. We discuss the integration of ctDNA methylation analysis with traditional imaging and clinical data to enhance the early detection of IPNs, as well as potential solutions to address the challenges of low biomarker concentration and background noise. By advancing precision diagnostics, liquid biopsy technologies could transform lung cancer management, improve survival rates, and reduce the disease burden.