Macrophage and monocyte subsets as new therapeutic targets in cancer immunotherapy

The introduction of immune checkpoint inhibitors (ICIs) for the treatment of solid cancers dramatically turned the tables in clinical routine. However, therapy success is still limited with up to 70% of non-responders in patients with ICI treatment. Traditionally, most immunotherapy approaches aim at directly stimulating anti-tumor T cell responses. More recently, tumor-associated macrophages have come into focus due to their predominance in solid tumors. Intensive cross-talk with tumor cells and immune as well as stromal cells within the tumor microenvironment can drive either pro- or anti-tumorigenic macrophage phenotypes. In turn, tumor-associated macrophages strongly shape cytokine and metabolite levels in the tumor microenvironment and thus are central players in anti-tumor immunity. Thus, ambivalent macrophage populations exist which raises therapeutic possibilities to either enhance or diminish their functionality. However, molecular signals controlling tumor-associated macrophage polarization are incompletely understood. Gaining in-depth understanding of monocyte/macrophage properties both in circulation and within distinct tumor microenvironments would (i) allow the development of new therapeutic approaches, and (ii) could additionally aid our understanding of underlying mechanisms limiting current therapy with the option of combinatorial therapies to increase efficacy. In this review, we summarize recent data addressing heterogeneity of tumor-associated macrophage populations and we discuss strategies to target macrophages using known molecular pathways with the potential for straight-forward clinical application.

Automated summary

The introduction of immune checkpoint inhibitors (ICIs) has greatly changed the landscape of clinical routine for solid cancer treatment. However, many patients do not respond well to ICI treatment. Traditional immunotherapy approaches focus on stimulating anti-tumor T cell responses, but recent attention has shifted to tumor-associated macrophages as they play a crucial role in the tumor microenvironment. The polarization of tumor-associated macrophages is influenced by intensive cross-talk with various cells, which can either promote or inhibit tumorigenic activity. Further understanding of the molecular signals controlling macrophage polarization may lead to the development of new therapeutic approaches and potential combination therapies to improve efficacy.