Gab2 promotes the growth of colorectal cancer by regulating the M2 polarization of tumor-associated macrophages

Tumor-associated macrophages (TAMs) are pivotal components in colorectal cancer (CRC) progression, markedly influencing the tumor microenvironment through their polarization into the pro-inflammatory M1 or pro-tumorigenic M2 phenotypes. Recent studies have highlighted that the Grb2-associated binder 2 (Gab2) is a critical gene involved in the development of various types of tumor, including CRC. However, the precise role of Gab2 in mediating TAM polarization remains incompletely elucidated. In the present study, it was discovered that Gab2 was highly expressed within CRC tissue TAMs, and was associated with a poor prognosis of patients with CRC. Functionally, it was identified that the tumor-conditioned medium (TCM) induced Gab2 expression, facilitating the TAMs towards an M2-like phenotype polarization. Of note, the suppression of Gab2 expression using shRNA markedly inhibited the TCM-induced expression of M2-associated molecules, without affecting M1-type markers. Furthermore, the xenotransplantation model demonstrated that Gab2 deficiency in TAMs inhibited tumor growth in the mouse model of CRC. Mechanistically, Gab2 induced the M2 polarization of TAMs by regulating the AKT and ERK signaling pathways, promoting CRC growth and metastasis. In summary, the present study study elucidates that decreasing Gab2 expression hinders the transition of TAMs towards the M2 phenotype, thereby suppressing the growth of CRC. The exploration of the regulatory mechanisms of Gab2 in TAM polarization may enhance the current understanding of the core molecular pathways of CRC development and may thus provide a foundation for the development of novel immunotherapeutic strategies targeted against TAMs.