IGF2BP2 Deficiency in Macrophages Impairs Migration, Reprograms Metabolism, and Limits Tumor Progression

While insulin-like growth factor 2 mRNA-binding protein 2 (IGF2BP2) has been extensively studied in tumor cells, its role in immune cells within the tumor microenvironment, particularly in macrophages, remains largely unknown. Here, we reveal a critical function of IGF2BP2 in macrophages, demonstrating that myeloid-specific deletion of IGF2BP2 profoundly alters macrophage metabolism and polarization, and markedly impairs tumor progression. Bulk RNA sequencing of IGF2BP2 knockout (KO) macrophages revealed significant alterations in gene expression profiles, particularly impacting pathways associated with glycolysis, mitochondrial function, cell motility, and cell migration. Functional assays confirmed increased glycolytic activity and a concomitant reduction in maximal respiration and reserve respiratory capacity, indicating a metabolic shift towards glycolysis. Furthermore, IGF2BP2 deficiency impaired tumor-associated macrophage (TAM)-like polarization in vitro, as evidenced by decreased expression of TAM markers, such as Mrc1, Mmp2, and Il10. Lipidomic profiling revealed distinct lipid signatures in IGF2BP2 KO TAM-like macrophages, including alterations in triglycerides and cardiolipins, crucial for mitochondrial integrity. In vivo, deletion of IGF2BP2 specifically in the myeloid lineage was sufficient to reduce tumor growth in a subcutaneous Lewis lung carcinoma model, accompanied by decreased TAM infiltration and a shift towards a pro-inflammatory macrophage phenotype. Additionally, IGF2BP2-deficient macrophages showed impaired migratory capacity both in vitro and in vivo. These findings underscore the critical role of IGF2BP2 in controlling macrophage metabolism, polarization, and tumor-supporting functions within the tumor microenvironment, and identify myeloid IGF2BP2 as a potential therapeutic target in cancer.