Liquid biopsy across cancers: Integrating circulating biomarkers, tumor biology, artificial intelligence, and clinical translation

Liquid biopsy has emerged as a minimally invasive approach for cancer detection and monitoring, with circulating tumor DNA (ctDNA) as its most clinically developed component. However, its performance is inconsistent across cancer types and clinical settings. In some cases, ctDNA is readily detectable, whereas in others, it remains present at very low levels or is not detected. While this variability is often attributed to technical limitations, it is increasingly clear that tumor biology, particularly the dynamics of DNA shedding into circulation, plays a major role. In this review, we place ctDNA within the broader context of circulating biomarkers rather than considering it in isolation. We discuss the biological processes that influence ctDNA release, fragmentation, and clearance, including tumor cell turnover and cell death pathways, as these directly affect its abundance in blood. We revisit key clinical applications, including early detection, minimal residual disease assessment, treatment monitoring, and resistance profiling, from this perspective. Across lung, colorectal, breast, and ovarian cancers, differences in tumor biology appear to align closely with how ctDNA performs in each setting. We also highlight the potential of multi‐omic approaches and computational methods to improve the interpretation of circulating signals and support clinical translation.