S1PR1‐Overexpressing Membrane‐Coated Nanoparticles Inhibit Dedifferentiation Progression for the Treatment of Anaplastic Thyroid Carcinoma by Targeting the ACER3/SPHK1/S1P Pathway

Anaplastic thyroid carcinoma (ATC) is a highly aggressive malignancy with a poor prognosis, characterized by dedifferentiation and aberrant angiogenesis. Through integrated analysis of TCGA and GEO transcriptomic data and single-cell RNA sequencing, this study identified significant enrichment of angiogenesis-related genes (ARGs), particularly sphingosine kinase 1 (SPHK1), in malignant cell subpopulations of ATC. Functional investigations revealed that alkaline ceramidase 3 (ACER3) cooperates with SPHK1 within the sphingolipid metabolic pathway to promote ATC progression. The SPHK1-specific inhibitor PF543 suppresses the activity of this key protein, thereby exhibiting potential therapeutic effects. To address the poor aqueous solubility and limited targeting ability of PF543, we constructed biomimetic nanoparticles (CMOE@PLGA@PF543) coated with S1PR1-overexpressing cancer cell membranes (CMOE), enabling tumor-specific targeting through the sphingosine-1-phosphate (S1P) and sphingosine-1-phosphate receptor 1 (S1PR1) ligand-receptor interaction. In vitro, PF543 downregulated SPHK1 expression and induced apoptosis in ATC cells. In vivo, CMOE@PLGA@PF543 exhibited enhanced tumor-targeting accumulation, excellent biosafety, and potent inhibition of tumor growth by suppressing the ACER3/SPHK1/S1P axis. These findings reveal a novel molecular mechanism driving ATC progression and offer a targeted nanotherapeutic strategy with strong potential for clinical translation.