Blood-based tumor biomarkers: integrating biological layers and analytical strategies for precision cancer detection

Blood-based cancer biomarkers promise minimally invasive, longitudinal monitoring, yet their clinical utility varies profoundly by analyte class, disease stage, and analytical methodology. This Review critically evaluates six circulating biomarker classes, such as CTCs, ctDNA, cfDNA methylation, exosomes, circulating miRNAs, and tumor-educated platelets-moving beyond a descriptive catalog to a comparative analysis of their performance characteristics. We find that the dominant challenge is no longer signal detection per se, but rather signal interpretation in the presence of biological confounders like clonal hematopoiesis and pre-analytical variability. We argue that a disciplined pairing of a biomarker's biological origin with the physico-chemical principles of its detection platform is the primary determinant of assay robustness. The Review concludes by outlining a pragmatic framework for integrating orthogonal biomarker readouts, emphasizing that how we combine signals is a more pressing question than how many markers we can measure.