Abstract: Thyroid cancer (TC), the most prevalent endocrine malignancy worldwide, encompasses a broad spectrum of biological behaviors ranging from indolent microcarcinomas to lethal anaplastic variants. Despite advancements in standard care, critical clinical “bottlenecks” persist, including the diagnostic ambiguity of Bethesda III/IV nodules, the rising prevalence of radioiodine-refractory (RAI-R) differentiated TC, and the dismal survival rates of anaplastic thyroid carcinoma (ATC). The rapid evolution of biomarkers has catalyzed a paradigm shift from traditional anatomical-pathological staging to a sophisticated “Molecular Taxonomy” model, providing the cornerstone for precision oncology. This review systematically delineates the multi-dimensional landscape of TC biomarkers, encompassing genomic and transcriptomic drivers (eg, BRAF, RAS, TERT, RET, NTRK), epigenetic regulators (miRNAs, lncRNAs, circRNAs, and DNA methylation), and the proteomic interface. We highlight the transformative role of Liquid Biopsy 2.0-including ctDNA-based minimal residual disease (MRD) detection and exosomal multi-omics-in enabling non-invasive, longitudinal surveillance. Furthermore, we explore how cutting-edge technologies, such as single-cell sequencing and spatial transcriptomics, are deciphering intratumoral heterogeneity and redefining the “functional invasive front”. Clinical translation is addressed through the lens of personalized management: from the use of genomic classifiers (eg, ThyroSeq v3) in preoperative triage to biomarker-guided “de-escalation” or “intensification” of therapy. Finally, we discuss the imperative of addressing ancestry-specific molecular divergence (specifically in Asian cohorts). However, significant challenges remain, including the high cost of multi-omics integration and the lack of standardized protocols for clinical implementation. We conclude by envisioning a future integrated with multimodal AI models, patient-derived organoids (PDOs), and metabolic reprogramming markers, aiming to provide a holistic framework for the “early screening-precise diagnosis-tailored therapy-dynamic monitoring” continuum in thyroid oncology. Keywords: thyroid cancer, precision oncology, molecular taxonomy, liquid biopsy, tumor microenvironment, spatial transcriptomics, clonal evolution, multi-modal artificial intelligence, radioiodine refractoriness, ancestry-specific medicine
Huang et al. (Fri,) studied this question.