Abstract
To elucidate the immunological mechanisms underlying T cell exhaustion in papillary thyroid carcinoma (PTC) by integrating bulk and single-cell transcriptomic data, with a particular focus on the NECTIN-TIGIT interaction as a potential driver of immune evasion. Papillary thyroid carcinoma, while often indolent, can recur or progress in certain patients. Increasing evidence suggests that immune evasion within the tumor microenvironment (TME) plays a central role in PTC pathogenesis. Among the various immune checkpoint pathways, the NECTIN-TIGIT axis has emerged in other cancers as a key mediator of T cell dysfunction; yet, its role in PTC remains poorly characterized. We conducted an integrated analysis of publicly available bulk RNA-sequencing and single-cell RNA-sequencing (scRNA-seq) datasets from the gene expression omnibus (GEO). Differential gene expression, cell-type annotation, exhaustion marker profiling, and ligand-receptor interaction analyses were employed to investigate immune cell states and intercellular signaling. Drug sensitivity data from multiple pharmacogenomic databases were used to assess therapeutic implications. Our analysis revealed a high expression of TIGIT and associated exhaustion markers (PDCD1, CTLA4, and TOX) in PTC-infiltrating T cells, alongside a dominant presence of NECTIN2/3 in epithelial and endothelial compartments. The NECTIN-TIGIT interaction was found to suppress CD226 co-stimulatory signaling, promoting T cell exhaustion. Endothelial cells were identified as key ligands senders, creating an immunosuppressive microenvironment. Drug sensitivity correlations further suggested that TIGIT-mediated exhaustion may influence therapeutic responsiveness. This study identifies the NECTIN-TIGIT axis as a novel immunoregulatory pathway contributing to T cell exhaustion in PTC. These findings provide mechanistic insights into immune evasion and suggest NECTIN-TIGIT signaling as a potential biomarker and therapeutic target. Future wet-laboratory validation and clinical studies are needed to confirm the translational relevance of this axis in thyroid cancer management.