Single-cell perspective on the Monocyte-to-HDL cholesterol ratio as a metastasis biomarker in papillary thyroid cancer.

[BACKGROUND] Papillary thyroid carcinoma (PTC) is a globally widespread inflammation-related cancer, where lymph node metastasis (LNM) poses significant challenges to the prognosis of PTC. The role of the monocyte-to-high-density lipoprotein cholesterol ratio (MHR), a novel inflammation marker attracting increasing attention, in PTC remains unclear.

[METHODS] Clinical data analysis was adopted to preliminarily explore the relationship between clinical features and LNM of PTC. Single-cell RNA sequencing (scRNA-seq) data from the GSE191288 and GSE193581 datasets were integrated to analyze various single-cell infiltration in PTC. A comprehensive suite of in vitro experiments, encompassing immunohistochemistry, co-culture, and Transwell assays were conducted to elucidate the regulatory role of macrophages and PTC.

[RESULTS] Clinical data analysis confirmed MHR could be an independent risk factor for LNM (OR = 1.76, 95%CI: 1.20-2.88, P = 0.011). The single-cell analysis identified cell clusters associated with dysregulated cholesterol homeostasis Q1 and CD68 + C3 macrophage subpopulations, as well as their markers GDF15. Further analysis confirmed that they are closely related to PTC metastasis and malignancy, which also implied a significant correlation between MHR and LNM. The in vitro experiments demonstrated PTC may promote metastasis by mediating inducing macrophage differentiation to the M2 phenotype.

[CONCLUSION] This study revealed the potential role of MHR in PTC from the single-cell perspective for the first time. Combined with the results of clinical studies and basic experiments, it was confirmed that mononuclear/macrophage and cholesterol homeostasis significantly promoted the lymph node metastasis of PTC. Overall, these findings informed robust support for MHR as an emerging marker for preoperative LNM prediction of PTC.