Liquid Biopsy in CRC Management: Early Detection, Minimal Residual Disease, and Therapy Optimization—Clinical Evidence and Challenges

ABSTRACT Colorectal cancer (CRC) is a major global health burden, ranking among the leading causes of cancer‐related deaths. Despite improvements in screening and treatment, challenges such as late‐stage diagnosis, high recurrence rates, and therapy resistance continue to impede optimal outcomes. Liquid biopsy, a minimally invasive technique that analyzes tumor‐derived components in bodily fluids—including circulating tumor DNA (ctDNA), circulating tumor cells (CTCs), and extracellular vesicles (EVs)—is emerging as a powerful tool to transform CRC management across the disease continuum. This review provides a comprehensive overview of liquid biopsy's current and emerging applications in CRC. We examine its role in early detection, where sensitive ctDNA‐based assays and epigenetic biomarkers have demonstrated the ability to identify CRC at asymptomatic or early stages, potentially improving screening uptake and compliance. Furthermore, we explore how liquid biopsy enables dynamic monitoring of treatment response and clonal evolution, facilitating the timely identification of resistance mutations and supporting personalized therapy adjustments. Innovations in multi‐omics integration, artificial intelligence, and ultra‐sensitive sequencing technologies are also discussed as pivotal advancements that enhance the clinical utility of liquid biopsy. Despite significant progress, the widespread adoption of liquid biopsy faces several hurdles, including assay standardization, sensitivity for low‐shedding tumors, regulatory approval, and cost‐effectiveness. Continued research, validation in large prospective trials, and harmonization of testing protocols are essential to overcome these challenges. Ultimately, liquid biopsy holds the potential to become a cornerstone of precision oncology in CRC, enabling earlier intervention, more tailored treatment strategies, and improved patient outcomes.