Exhaled Breath Analysis for Lung Cancer Detection: From VOCs Signatures to EBC-Based Liquid Biopsy and Clinical Translation

Lung cancer remains the leading cause of cancer-related mortality globally. Although low-dose computed tomography (LDCT) is the current standard for early screening, its high false-positive rates and cumulative radiation exposure create a pressing clinical need for complementary, non-invasive diagnostic tools. Exhaled breath analysis represents an accessible strategy for early detection and risk stratification. Early breathomics primarily focused on gas-phase volatile organic compounds (VOCs). However, as volatile metabolites, VOCs are chemically unstable and highly susceptible to background ambient air and physiological confounders. Distinct from gas-phase analysis, exhaled breath condensate (EBC) offers enhanced biomarker stability and functions as a lung-proximal liquid biopsy. By capturing non-volatile, high-molecular-weight analytes, including tumor-derived nucleic acids and proteins, EBC more closely reflects the underlying molecular mechanisms of the respiratory microenvironment. Nevertheless, the clinical translation of EBC remains constrained by severe sample dilution, unstandardized collection device architectures, and pre-analytical inconsistencies. This review summarizes the progression from VOCs profiling to EBC-based platforms, detailing recent advances in sample harvesting, ultrasensitive detection technologies, and multi-omics integration. Advancing EBC toward routine clinical use requires consensus-driven standard operating procedures and the application of machine learning algorithms to high-dimensional datasets. Future efforts should prioritize large-scale, multicenter prospective trials to validate specific EBC signatures, thereby establishing this technology as a reliable liquid biopsy for precision pulmonary oncology.