Label-Free Cancer Detection Methods Based on Biophysical Cell Phenotypes

The progress of clinical diagnosis increasingly relies on innovative technologies and advanced disease biomarker detection methods. While cell labelling remains a well-established technique, label-free approaches offer significant advantages, including reduced workload, minimal sample damage, cost-effectiveness, and simplified chip integration. These approaches focus on the morpho-biophysical properties of cells, eliminating the need for labeling and thus reducing false results while enhancing data reliability and reproducibility. Current label-free methods span conventional and advanced technologies, including phase-contrast microscopy, holographic microscopy, varied cytometries, microfluidics, dynamic light scattering, atomic force microscopy, and electrical impedance spectroscopy. Their integration with artificial intelligence further enhances their utility, enabling rapid, non-invasive cell identification, dynamic cellular interaction monitoring, and electro-mechanical and morphological cues analysis, making them particularly valuable for cancer diagnostics, monitoring, and prognosis. This review compiles recent label-free cancer cell detection developments within clinical and bio-technological laboratory contexts, emphasizing biophysical alterations pertinent to liquid biopsy applications. It highlights interdisciplinary innovations that allow the characterization and potential identification of cancer cells without labelling. Furthermore, a comparative analysis addresses throughput, resolution, and detection capabilities, thereby guiding their effective deployment in biomedical research and clinical oncology settings.