Single‐Cell Transcriptomics Reveals ITGA2‐Mediated Metabolic Reprogramming and Immune Crosstalk in Pediatric Thyroid Carcinogenesis

Pediatric papillary thyroid carcinoma (PPTC) has exhibited a progressive increase in incidence in recent years, characterized by heightened biological aggressiveness relative to adult papillary thyroid carcinoma (APTC). Nevertheless, the molecular mechanisms governing PPTC-specific pathobiology remain elusive. Through high-resolution single-cell RNA sequencing analysis of 90234 cellular transcriptomes from 4 PPTC and 9 APTC clinical specimens, a phenotypically distinct cellular subpopulation (ITGA2^hi-PTC cells) mechanistically responsible for PPTC's distinct clinical behavior, is identified. By integrating PPTC-derived organoid models with in vivo functional validation and multiplex immunohistochemistry, it is demonstrated that ITGA2 orchestrates dual oncogenic pathways: 1) augmentation of glycolytic flux and 2) induction of M2 macrophage polarization. These synergistic mechanisms fundamentally drive PPTC oncogenesis and metastatic progression. Cross-validation across independent clinical cohorts consistently confirms the translational significance of these findings. Our multi-omics characterization of PPTC-specific cellular ecosystems and signaling cascades establishes a mechanistic framework for advancing diagnostic precision and targeted therapeutic development.