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

Papillary thyroid carcinoma (PTC) is the most common thyroid malignancy, with some cases exhibiting aggressive features and therapeutic resistance. Dysregulated protein interaction networks and remodeling of the immune microenvironment have been increasingly recognized as critical in PTC progression. However, the genetic, protein, and immune regulatory networks involved in PTC have yet to be systematically elucidated. To address this gap, we employed an integrated multi-omics and genetic epidemiological approach. This study employed a multi-stage integrated analysis strategy combining Mendelian randomization (MR), mediation analysis, and bioinformatics validation. First, MR was applied using protein quantitative trait loci (pQTL) data from the deCODE and UK Biobank Pharma Proteomics Project (UKB-PPP) databases, together with PTC genome-wide association study (GWAS) data from FinnGen, to screen for PTC-associated proteins. Second, a two-step mediation analysis was conducted to construct protein–protein interaction (PPI) networks and immune microenvironment regulatory networks. Finally, differential expression and co-expression analyses were performed using The Cancer Genome Atlas (TCGA) and Genotype-Tissue Expression (GTEx) databases to validate the functional relevance of the identified networks. We identified the ITGB2 (integrin β2)-IL2RB (interleukin-2 receptor β)-natural killer (NK) cell regulatory axis, which was significantly associated with PTC risk. This regulatory axis exhibited marked differential expression and co-expression relationships in PTC tissues, confirming its functional relevance. This study establishes a causal regulatory chain of "ITGB2-IL2RB-NK cell" in PTC through integrated multi-omics and genetic epidemiological approaches. This work provides a theoretical basis for developing combined immunotherapy strategies targeting components of the ITGB2-IL2RB-NK cell regulatory axis within the tumor microenvironment.