Surface-enhanced Raman spectroscopy for label-free cancer liquid biopsy: from fundamentals to clinical analysis of biofluid

Cancer remains one of the major public health problems due to its high morbidity and mortality globally. Because metastasis is the major cause of cancer death, developing new approaches for early diagnosis is of paramount importance in this context. Surface-enhanced Raman scattering (SERS) has emerged as a cutting-edge analytical technique. SERS features an exceptional sensitivity and specificity, enabling rapid non-destructive detection of trace-level samples. Therefore, SERS technology is widely used across medical disciplines, particularly in cancer diagnosis for early-stage and non-invasive diagnostic evaluation. Using liquid biopsy with rich metabolic information, SERS has facilitated the identification, analysis, and progression monitoring of various cancers. In this review, we systematically summarize recent advances in label-free SERS-based cancer diagnostics. We first outline the fundamental principles of SERS, key substrate fabrication methodologies, and essential spectral analysis techniques. We then highlight the applications of label-free SERS in liquid biopsy using various biofluids, including blood, urine, saliva, and sweat. Finally, we discuss current challenges and future directions in this rapidly evolving field.