Perithyroidal Adipose Tissue Drives Thyroid Tumorigenesis through Adipokine Signaling and Immune Suppression

The perithyroidal adipose tissue (PAT), given its direct anatomical proximity to the thyroid gland, has long been postulated as a modulator of the thyroid tumor microenvironment. However, its cellular composition, functional heterogeneity, and specific roles in thyroid cancer progression remain unknown. To address these knowledge gap, we performed single-nucleus RNA sequencing of PAT from patients with papillary thyroid carcinoma (PTC) and multinodular goiter (MNG), combined with machine learning, proteomics, immunofluorescence, ex vivo assays, and human serum analysis. We constructed the first high-resolution atlas of human PAT, revealing an immune-rich niche and previously unrecognized adipocyte heterogeneity, including thermogenic subpopulations (BL-Ad1, BL-Ad2, OXPHOS-Ad) from distinct progenitors. Functionally, the PAT secretome from PTC substantially enhanced thyroid cancer cell proliferation compared to MNG. Integrated analyses identified a pathogenic adipokine triad characterized by loss of ADIPOQ and gain of NAMPT and IGF1. Restoring ADIPOQ signaling or inhibiting NAMPT/IGF1 suppressed tumor growth in vitro and in vivo. Additionally, we identified CCL14, down-regulated in PTC-derived OXPHOS-Ad, as a key immune regulator. Reduced CCL14-CCR1 signaling impaired CD80 expression in M1-like macrophages, disrupting CD80-CD28 costimulation and consequently diminishing T cell proliferation and recruitment. Consistently, circulating CCL14 levels were reduced in PTC patients. In conclusion, PAT acts as a dynamic endocrine and immunomodulatory component of the tumor microenvironment that promotes thyroid tumor growth through adipokine-mediated and immune-dependent mechanisms.