From spectroscopic analysis to clinical imaging: emerging applications and persistent challenges of raman spectroscopy in CTCs-based liquid biopsies

Current cancer diagnosis relies on established tools such as serum biomarkers, imaging, and tissue biopsies. However, their limitations-including inadequate sensitivity for early detection, invasiveness, and inability to capture real-time dynamics-highlight the critical need for more reliable, minimally invasive technologies. This review focuses on circulating tumor cells (CTCs) as a liquid biopsy cornerstone, emphasizing their unique biological characteristics and clinical potential. CTCs, shed from primary or metastatic tumors into the bloodstream, enable minimally invasive and serial sampling. They hold significant promise for early diagnosis, prognosis, heterogeneity assessment, and therapeutic monitoring. Concurrently, Raman imaging, a powerful label-free optical technique, provides intrinsic molecular fingerprinting with high chemical specificity. Its biomedical applications, from immune cell profiling to tumor margin detection, are well-established. Recent advances, particularly in single-cell Raman spectroscopy, now enable real-time, non-destructive analysis of rare cells, creating novel opportunities for CTC research. This article systematically examines CTC biology and heterogeneity, Raman imaging principles [including Surface-Enhanced Raman Scattering (SERS) and Tip-Enhanced Raman Scattering (TERS)], and their specific applications in CTC detection and characterization. We synthesize the latest progress in Raman-based platforms for CTC analysis and discuss current challenges and future trajectories for integrating Raman imaging into standardized liquid biopsy workflows for oncology.