Sputum Liquid Biopsy for Lung Cancer Screening, Diagnosis, Subtyping, Surveillance, Response Prediction, and Prognostication: A Scoping Review

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Abstract
Background/Objectives: Liquid biopsy (LB) is transforming cancer care by enabling minimally invasive tumor profiling. While current research and clinical pathways mostly focus on blood LB, sputum represents a non-invasive, readily available respiratory specimen that may offer unique advantages for lung cancer (LC) care. Despite its potential, the maturity, breadth, and clinical applicability of sputum-based LB remain elusive. Methods: We conducted a scoping review to systematically map the existing literature on sputum LB in LC. Electronic databases were searched for studies evaluating sputum-derived biomarkers—cytologic, genomic, epigenetic, transcriptomic, proteomic, metabolomic, metagenomic, and extracellular vesicle–derived products—across the LC care continuum. Study designs, technologies, clinical contexts, and reported outcomes were extracted and synthesized qualitatively. Results: The literature demonstrated substantial heterogeneity in sputum collection, processing, and analytical platforms. Early work focused on cytometry and genetic alterations, while recent studies increasingly explore DNA methylomics, microRNAs, extracellular vesicle-derived products, and multi-omics approaches. The evidence suggests potential utility of sputum biomarkers for early detection and risk stratification, particularly in high-risk populations, with emerging data supporting roles in molecular subtyping, response monitoring, prognostication, and surveillance. However, few studies report prospective validation, direct comparison with blood-based LB, or impact on actual patient outcomes. Conclusions: Sputum LB is a promising yet underdeveloped modality in LC care. This scoping review highlights technological innovations alongside significant methodological heterogeneity and translational gaps. Future research should focus on standardization, prospective validation, impact on patient outcomes, and integration with blood- and other body fluid–based LB, as well as imaging biomarkers. This will enable incorporation of sputum-based LB into actual clinical pathways of LC care.

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