LAUSR

Significance Macrophages can be functionally reprogrammed by the tumor microenvironment to further tumor growth and malignancy. In this study, we have discovered that this pathological process is dependent on the ERK5 MAPK. Accordingly, we demonstrated that inactivation of ERK5 in macrophages blocked the phosphorylation of STAT3, a transcription factor crucial for determining macrophage polarity, and impaired the growth of melanoma and carcinoma grafts. These results raise the possibility that targeting protumor macrophages via anti-ERK5 therapy constitutes a very attractive strategy for cancer treatment. This is important given that the detection of large numbers of macrophages in human tumors often correlates with poor prognosis, but also with a poor response of the tumor to anticancer agents. Owing to the prevalence of tumor-associated macrophages (TAMs) in cancer and their unique influence upon disease progression and malignancy, macrophage-targeted interventions have attracted notable attention in cancer immunotherapy. However, tractable targets to reduce TAM activities remain very few and far between because the signaling mechanisms underpinning protumor macrophage phenotypes are largely unknown. Here, we have investigated the role of the extracellular-regulated protein kinase 5 (ERK5) as a determinant of macrophage polarity. We report that the growth of carcinoma grafts was halted in myeloid ERK5-deficient mice. Coincidentally, targeting ERK5 in macrophages induced a transcriptional switch in favor of proinflammatory mediators. Further molecular analyses demonstrated that activation of the signal transducer and activator of transcription 3 (STAT3) via Tyr705 phosphorylation was impaired in erk5-deleted TAMs. Our study thus suggests that blocking ERK5 constitutes a treatment strategy to reprogram macrophages toward an antitumor state by inhibiting STAT3-induced gene expression.