The liquid biopsy has gained significant attention in cancer diagnostics, with circulating tumor cells (CTCs) and circulating tumor DNA (ctDNA) being recognized as key biomarkers for tumor detection and monitoring. However, each biomarker possesses inherent limitations that restrict its standalone clinical utility, such as the rarity and heterogeneity of CTCs and the variable sensitivity and specificity of ctDNA assays. This highlights the necessity of integrating both biomarkers to maximize diagnostic and prognostic potential, offering a more comprehensive understanding of the tumor biology and therapeutic response. In this review, we summarize clinical studies that have explored the combined analysis of CTCs and ctDNA as biomarkers, providing insights into their synergistic value in diverse tumor types. Specifically, this paper examines the individual advantages and limitations of CTCs and ctDNA, details the findings of combined biomarker studies across various cancers, highlights the benefits of dual biomarker approaches over single-biomarker strategies, and discusses future prospects for advancing personalized oncology through liquid biopsies. By offering a comprehensive overview of clinical studies combining CTCs and ctDNA, this review serves as a guideline for researchers and clinicians aiming to enhance biomarker-based strategies in oncology and informs biosensor design for improved biomarker detection.

Serum alpha-fetoprotein (AFP) is widely used for hepatocellular carcinoma (HCC) management, yet its limited sensitivity and specificity restrict diagnostic and prognostic utility. In this study, we explore the clinical potential of AFP quantification from cell-free DNA (cfDNA) and circulating tumor cells (CTCs) using a novel bead-based liquid biopsy platform. Following isolation, AFP abundance in cfDNA was quantified by qPCR, while AFP protein expression in CTCs was assessed via immunohistochemistry. Compared to serum AFP, cfDNA-derived AFP demonstrated significantly greater diagnostic accuracy in distinguishing HCC patients from non-cancerous individuals (p < 0.0001, AUC = 0.998), while AFP⁺ CTCs showed high specificity. Post-treatment changes in AFP levels from cfDNA and CTCs were significantly associated with therapeutic response and overall survival, outperforming conventional serum AFP. Longitudinal monitoring further revealed that cfDNA AFP levels reliably captured recurrence events prior to clinical diagnosis. Moreover, a combined metric integrating AFP levels from cfDNA and CTCs significantly improved response stratification (AUC = 0.89), outperforming individual biomarkers. This pilot study highlights the potential of multimodal AFP profiling through cfDNA and CTCs as a promising, non-invasive approach for enhancing diagnosis, prognosis, and treatment monitoring in HCC, with direct implications for personalized therapeutic strategies.