Investigating the Role of TNFSF12 in Thyroid Cancer Progression via Single-Cell RNA Sequencing and Integrated Multiomics Analyses.

[BACKGROUND] Thyroid carcinoma is characterized by significant heterogeneity and immune evasion, in which myeloid cells play a pivotal role in tumor microenvironment (TME) remodeling. However, the key regulatory genes and their underlying mechanisms are not yet fully elucidated.

[OBJECTIVE] This study aims to identify and validate critical myeloid-derived genes involved in driving thyroid cancer progression by employing an integrated multiomics approach.

[METHODS] We performed single-cell RNA sequencing (scRNA-seq) on thyroid cancer tissues, integrated with High-dimensional weighted gene co-expression network analysis (hdWGCNA) for coexpression module identification, Mendelian randomization (MR) for causal inference, and functional validation assays in thyroid carcinoma cell lines including qPCR, CCK-8, colony formation, and transwell assays. Microbial correlation analysis and molecular docking were additionally conducted to explore potential interactions.

[RESULTS] We identified a tumor-specific myeloid subpopulation (C5) and a disease-associated coexpression module harboring three hub genes: MERTK, MSR1, and TNFSF12. MR analysis confirmed MERTK and MSR1 as genetic risk factors for thyroid cancer progression, whereas TNFSF12 exhibited protective effects. Functional experiments demonstrated that TNFSF12 enhances proliferative, invasive, and migratory capacities in thyroid cancer cells. Furthermore, MSR1 and MERTK were found to be significantly correlated with specific intratumoral microbiota and associated with BRAF mutation and response to immunotherapy.

[CONCLUSION] Our study reveals a myeloid-centered regulatory network in thyroid cancer and highlights TNFSF12 as a context-dependent oncogene, offering novel insights into targeted therapy and immunotherapeutic strategies.