USP7 induces macrophage M2 polarization to promote thyroid cancer through binding to m6A-modified SDC4 mRNA to promote SDC4 expression via deubiquitinating IGF2BP2

The present study explored the regulatory mechanism by which USP7/IGF2BP2/SDC4 influences thyroid cancer (THCA) progression based on macrophage M2 polarization. This study was based on four levels—bioinformatics analysis, clinical validation, in vitro cellular study, and in vivo study in nude mice—and adopted multiple scientific detection methods to investigate the impact of USP7/IGF2BP2/SDC4 on macrophage M2 polarization in THCA. Bioinformatics analysis showed differentially expressed IGF2BP2 in THCA, and association between high USP7 expression and poor survival in THCA patients. IGF2BP2 could recognize m6A modification sites of SDC4. USP7, IGF2BP2 and SDC4 proteins were aberrantly overexpressed within clinical THCA tissues, especially within M2 macrophages. By in vitro study, IGF2BP2 up-regulated SDC4 protein within THP-1 cells, which was neutralized by 3-DAA—inhibitor of m6A methylation. IGF2BP2 enhanced macrophage M2 polarization and SDC4 protein in macrophages co-cultured with THCA cells, but was abrogated by SDC4 silencing. USP7 could up-regulate IGF2BP2 within THCA cells by deubiquitination. In macrophages co-cultured with THCA cells, IGF2BP2 intensified macrophage M2 polarization, while USP7 silencing attenuated macrophage M2 polarization and IGF2BP2 expression. Through in vivo research, IGF2BP2 in macrophages facilitated THCA cell growth and macrophage M2 polarization in xenograft tumor tissues, which was abolished by silencing of SDC4 or USP7. USP7 induced macrophage M2 polarization to drive THCA progression, potentially by binding to m6A-modified SDC4 mRNA to stable SDC4 expression via deubiquitinating IGF2BP2. Targeted inhibition of USP7, IGF2BP2 and SDC4 might be a promising approach for treating THCA. In macrophages infiltrating thyroid cancer tissues, elevated levels of the deubiquitinase USP7 lead to reduced ubiquitination of the IGF2BP2 protein, thereby inhibiting its degradation. IGF2BP2 then recognizes and binds to m6A-methylated SDC4 mRNA, enhancing the stability of SDC4 mRNA and promoting SDC4 expression. This subsequently induces M2 polarization and contributes to immunosuppression in thyroid cancer.