MerTK inhibitor suppresses melanoma growth in mice by regulating the quantity and phe-notype of tumor-associated macrophages

WU Naming; SHA Shanshan; YANG Liu

doi:10.3969/j.issn.1674-8468.2025.07.001

Abstract：Objective To investigate the effect of the MerTK inhibitor UNC2250 on tumor growth in melanoma mice and to preliminarily elucidate its mechanism of action.Methods Six-teen healthy C57BL/6 mice were randomly divided into a control group and low-,medium-,and high-dose UNC2250 treatment groups,with 4 mice per group.After establishing a subcutaneous melanoma tumor model,the control group received daily oral gavage of saline,while the treatment groups were administered UNC2250 at doses of 25,50 and 75 mg/(kg·d),respectively,once daily for 20 consecutive days.Tumor growth,tumor weight,and body weight changes were moni-tored.The infiltration of tumor-associated macrophages(TAMs)in the tumor microenvironment was detected by immunofluorescence staining and flow cytometry.Additionally,bone marrow-de-rived macrophages(BMDMs)were cultured in vitro,and M2 macrophages were induced using IL-4.RT-PCR was used to evaluate the effect of UNC2250 on macrophage phenotype polarization.Results UNC2250 significantly inhibited tumor growth in melanoma mice in a dose-dependent manner(F=298.50,all P＜0.001).Compared with the control group,tumor weight in the low-,medium-,and high-dose UNC2250 treatment groups was significantly reduced(F=194.20,all P＜0.001),and tumor volume decreased with increasing doses.UNC2250 had no significant effect on body weight.Within the tumor microenvironment,UNC2250 intervention markedly reduced the infiltration of TAMs.Further analysis showed an increased proportion of M1-type macrophages among TAMs(F=31.95,P-values for comparisons with control group were 0.120,0.008,and＜0.001 for low,medium,and high doses,respectively),and a decreased proportion of M2-type macrophages(F=45.27;P-values were 0.034,＜0.001,and＜0.001,respectively).In vitro experiment showed that UNC2250 inhibited the polarization of bone marrow-derived macrophages(BMDMs)toward the immunosuppressive M2 phenotype,as evidenced by significantly downregulated mRNA expression of M2 macrophage markers Arg1 and Mgl1.Conclu-sions The MerTK inhibitor UNC2250 suppresses tumor growth in melanoma mice in a dose-de-pendent manner with good safety,and its intervention is associated with reduced infiltration of tumor-associated macrophages(TAMs)and a shift in macrophage polarization from the M2 to M1 phenotype in the tumor microenvironment.