Polypharmacological Re-programming of Tumor-associated Macrophages Restores Antitumor Immunity

Abstract

Tumor-associated macrophages (TAMs) are an important component of the tumor microenvironment (TME), and they promote tumor progression, metastasis, and resistance to therapies. However, although TAMs represent a promising target for therapeutic intervention, the complexity of TME has made the study of TAMs challenging. Here, we established a physiologically-relevant in vitro TAM polarization system that recapitulates TAM pro-tumoral activities. We used this system for phenotypic kinase inhibitor screening and identified a multi-targeted compound BMS-794833 as the most potent inhibitor of TAM polarization. BMS-794833 decreased pro-tumoral properties of TAMs and suppressed tumor growth in mouse triple-negative breast cancer models. The effect of BMS-794833 was not dependent on its primary targets (MET and VEGFR2) but on its effect on multiple signaling pathways, including focal adhesion kinases, SRC family kinases, STAT3, and p38 MAP kinases. Our study underlines the efficacy of polypharmacological strategies in re-programming complex signaling cascades activated during TAM polarization.