MD2 suppresses anaplastic thyroid Cancer progression by reprogramming macrophages via USP15-mediated FHL1 Deubiquitination.

Tumor-associated macrophages (TAMs), highly heterogeneous cells within the tumor microenvironment, can be broadly classified into anti-tumor M1 and pro-tumor M2 phenotypes. Myeloid differentiation protein 2 (MD2), a key immune regulator, has been demonstrated to modulate macrophage inflammatory responses. However, its involvement in TAM reprogramming and the subsequent impact on anaplastic thyroid cancer (ATC) progression remains unclear. In this study, we observed that ATC cells promote macrophage polarization toward the M2 phenotype, accompanied by reduced MD2 expression. Notably, MD2 upregulated the expression of USP15, which was subsequently proved to interact with four and a half LIM domains protein 1 (FHL1) and mediated its deubiquitination, leading to STAT3 inactivation and promoting macrophage polarization toward the M1 phenotype. Furthermore, overexpression of MD2 in macrophages significantly suppressed tumor growth and metastasis through TAM reprogramming. Collectively, these findings highlight a critical role of MD2 in regulating TAM polarization and suggest macrophage-targeted modulation of MD2 as a potential therapeutic strategy for ATC.