Integrated multi-omics reveals the ITGB2-IL2RB-NK axis in promoting papillary thyroid carcinoma progression and immune microenvironment crosstalk

Introduction : Papillary thyroid carcinoma (PTC) is the most common thyroid malignancy, with some cases exhibiting aggressive features and therapeutic resistance. Although dysregulated protein interaction networks and immune microenvironment remodeling have been increasingly recognized as critical in PTC progression, the specific genetic-protein-immune regulatory networks remain to be systematically elucidated. Methodology : This study adopted a multi-stage integrated analysis strategy combining Mendelian randomization (MR), mediation analysis, and bioinformatics validation. First, MR was applied using pQTL data from the deCODE and UKB-PP databases alongside PTC GWAS data from FinnGen to screen PTC-associated proteins. Second, a two-step mediation analysis was conducted to construct protein-protein-immune microenvironment regulatory networks. Finally, differential expression and co-expression analyses using The Cancer Genome Atlas (TCGA) and Genotype-Tissue Expression (GTEx) databases were performed to validate functional relevance. Results : We identified the ITGB2-IL2RB-NK cell regulatory axis, which was significantly associated with PTC risk. This regulatory axis demonstrated marked differential expression and co-expression relationships in PTC tissues, confirming its functional relevance. Conclusion : This study systematically revealed the tumor-promoting role of the ITGB2-IL2RB-NK cell axis in PTC for the first time, providing a theoretical basis for developing combined immunotherapy strategies targeting the tumor microenvironment.