Lymph‐based liquid biopsy: Current progress and future potential

Abstract The lymphatic system plays a pivotal role in both physiological and pathological processes. Lymphatic fluid, owing to its anatomical proximity to disease sites and rich composition of biomarkers, represents a promising source for liquid biopsy. Furthermore, emerging evidence under the revised Starling principle indicates that lymph‐based liquid biopsies may offer superior diagnostic performance over blood‐based counterparts in certain clinical scenarios, such as early‐stage solid tumor detection. In this comprehensive review, we systematically: compare the biochemical and cellular characteristics of lymph with those of other biofluids used in liquid biopsies, evaluate the clinical potential and current limitations of lymph‐based liquid biopsy, including available sampling techniques, and assess the diagnostic utility of lymph‐derived biomarkers across various disease contexts. Our analysis underscores that the primary challenge hindering broader clinical adoption is the lack of minimally invasive and clinically feasible lymphatic sampling methods. To advance translational applications, key developments are urgently needed in three areas: innovative sampling techniques, stringent quality control standards, and highly sensitive and accurate detection methodologies. This review aims to emphasize the value of lymphatic biomarkers in liquid biopsy and to stimulate further research and development in this emerging field.