Baicalin-loaded micelles: Modulating M1 macrophages to overcome Lenvatinib resistance in anaplastic thyroid carcinoma

Anaplastic thyroid carcinoma (ATC) is a highly aggressive tumor that frequently acquires resistance to targeted therapies, including Lenvatinib. Recent studies have emphasized the noteworthy influence of immune cells, particularly M1 macrophages, within the tumor microenvironment on tumor progression and drug responsiveness. This study aims to explore the potential of Baicalin-loaded polymer micelles (PMs) in reversing Lenvatinib resistance in ATC by modulating macrophage functionality and elucidating the underlying mechanisms.Utilizing the TCGA Thyroid Cancer (THCA) transcriptome dataset, differential gene expression analysis and immune infiltration assessments were conducted to identify differentially expressed genes (DGEs) and analyze M1 macrophage involvement. The Weighted Gene Co-expression Network Analysis (WGCNA) technique was further applied to pinpoint gene sets significantly linked to M1 macrophage infiltration, leveraging the abundance of M1 macrophages as a distinctive feature. By examining TC-related single-cell datasets from GEO, the cellular composition of TC tissues was delineated through rigorous quality control, dimensionality reduction, clustering, and annotation processes. Predictive tools such as PharMapper and the GeneCards database were utilized to predict baicalin targets and identify Lenvatinib-related genes, revealing intersecting pathways.In experimental settings, Lenvatinib-resistant ATC cells were cultured to investigate the impact of manipulating the MET gene and utilizing baicalin-PMs on macrophage behavior. The results demonstrated that these interventions substantially promoted M1 macrophage polarization and impeded the proliferation, migration, and invasion of the resistant cancer cells. Notably, in vivo experiments illustrated the efficacy of baicalin-PMs in suppressing M1 macrophage polarization and restraining tumor growth in the context of Lenvatinib resistance in ATC. Overall, the comprehensive multi-omics analysis underlines the potential of baicalin-PMs in reversing Lenvatinib resistance by modulating M1 macrophage function and inhibiting the MET factor, thus offering a novel strategy and target for combatting ATC resistance to Lenvatinib.