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

Abstract 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.