Zuojin Wan Suppresses the Progression of Colorectal Cancer by Inhibiting M2 Tumor-Associated Macrophages Through JAK2/STAT3 Signaling Pathway and In Vivo and In Vitro

Colorectal cancer (CRC) is a malignant tumor with high global incidence and mortality rates, often accompanied by an increase in M2 tumor-associated macrophages (TAMs), which may lead to poor prognosis in CRC patients. Zuojin Wan (ZJW), a traditional Chinese medicinal formula, has been demonstrated to have therapeutic effects on CRC. It can inhibit the proliferation of CRC cells and improve the prognosis of CRC by enhancing immunity; however, the precise immune mechanisms remain unclear. A CT26 cell-induced CRC tumor-bearing mouse model in this study was established to investigate the therapeutic effects of ZJW on CRC. In vivo experiments confirmed that ZJW significantly reduced the size of CRC tumors and decreased the levels of M2 TAMs markers, including CD206 and Arg-1, while increasing the levels of iNOS. Furthermore, in a co-culture system with macrophages, ZJW reduced the proportion of M2 macrophages and increased the proportion of M1 macrophages. Simultaneously, ZJW intervention attenuated the proliferation and migration of CT26 and MC38 cells. ZJW may suppress the migration and proliferation of CT26 and MC38 cells by inhibiting M2 TAMs. The results of network pharmacology combined with Western blot indicated that ZJW may suppress M2 TAMs by inhibiting JAK2/STAT3 signaling pathway in TAMs. This study confirmed that Zuojin Wan may suppress the malignant progression of colorectal cancer by inhibiting M2 TAMs, potentially mediated by inhibition of JAK2/STAT3 signaling pathway in TAMs.