Advances in electrochemical biosensing of CYFRA 21-1: Nanomaterial interfaces, molecular signal amplification, and emerging non-invasive cancer diagnostics.

The cytokeratin 19 fragment antigen (CYFRA 21-1) is a critical structural biomarker whose elevated expression is intrinsically linked to the progression of various epithelial-derived malignancies. Traditionally recognized as the "gold standard" circulating marker for non-small cell lung cancer (NSCLC), its clinical relevance extends to other squamous cell carcinomas, particularly oral squamous cell carcinoma (OSCC), where its presence in biological fluids reflects tumor activity and stage. Despite its clinical utility, routine quantification relies on conventional methodologies such as ELISA and chemiluminescence, which are limited by high operational costs, lengthy turnaround times, and dependence on centralized laboratory infrastructure. This review provides a critical synthesis of the recent advances in electrochemical biosensing as a disruptive alternative for CYFRA 21-1 monitoring. From a structural perspective, the review is organized around two main technological pillars: (i) advanced electrode/interface engineering based on emerging nanomaterials, and (ii) signal amplification strategies that enable ultrasensitive detection. Strategic interface engineering, employing MXenes, metal-organic Frameworks (MOFs), and 3D carbon nano-architectures, has enhanced bioreceptor immobilization and electron transfer kinetics. Signal amplification cascades, including DNA nanomachines (walkers and HCR) and eATRP, have further lowered detection limits to the attomolar range. By comparing these emerging technologies with established clinical standards, remaining challenges are highlighted, including long-term biosensor stability, resistance to electrode fouling, and scalable manufacturing, which must be addressed to translate these high-performance electrochemical platforms into robust, portable, point-of-care tools for routine oncological diagnostics. Harnessing the synergy of advanced nanomaterials and electronic integration, combined with non-invasive sampling such as unprocessed saliva, these next-generation sensors promise rapid, reliable, and accessible detection of CYFRA 21-1, ultimately improving patient management and clinical outcomes.