A Jak2-selective inhibitor potently reverses the immune suppression by modulating the tumor microenvironment for...

Small molecule therapeutics can be potent tools for cancer immunotherapy. They may be devised to target the tumor associated macrophages (TAMs) and regulatory T cells (Treg), which are major immunosuppressive cells in the tumor microenvironment. The infiltration and functionalization of these cells, which essentially promote tumor development, are mediated by the hyper-activation of the Jak-STAT3 signaling pathway. Here, we demonstrated that compound 9#, a novel inhibitor of Jak2, could suppress Jak2-STAT3 signaling in macrophages (peritoneal macrophages and THP-1 cells) and direct the macrophages toward the pro-inflammatory (M1-like) phenotype. When tested in ex vivo TAM culture and in vivo tumor models, compound 9# could reverse the phenotype of TAM from M2- to M1-type by promoting IL-12 expression. Further study suggested that compound 9# also inhibited the induction of Treg both in vitro and in vivo via blockage of Jak2 signaling. Finally, compound 9# potently increased the frequency and anti-tumor activity of CD4⁺ and CD8⁺ T lymphocytes, leading to effective suppression of tumor growth. Taken together, our findings indicated that compound 9# could be a potential candidate of small molecule therapeutics for cancer immunotherapy.