Macrophage immunotherapy: overcoming impediments to realize promise

The overuse and misuse of the macrophage ‘M1–M2 paradigm’ and the terms ‘inflammatory’ and ‘anti-inflammatory’ belie accurate description of macrophages and have hindered experimental design.The precise description of derived and isolated macrophages, including source, growth factors, stimuli, and culture conditions, is essential for developing macrophage-based immunotherapies.In vitro and in vivo studies are providing abundant proof-of-principle of the potential to harness macrophage activation to treat certain immune-related diseases.New advances, including derivation of macrophages from iPSCs, chimeric antigen receptor (CAR) macrophages, and Phase 1 clinical trials of ex vivo-derived macrophages might enable novel macrophage-based immunotherapies. While recognizing the heterogeneity of macrophages as well as the need for consistent nomenclature and characterization of macrophage sub-types, there is significant potential for harnessing macrophages for putative adoptive transfer therapies in various diseases. As an essential component of immunity, macrophages have key roles in mammalian host defense, tissue homeostasis, and repair, as well as in disease pathogenesis and pathophysiology. A source of fascination and extensive research, in this Opinion we challenge the utility of the M1–M2 paradigm, and discuss the importance of accurate characterization of human macrophages. We comment on the application of single cell analytics to define macrophage subpopulations and how this could advance therapeutic options. We argue that human macrophage cell therapy can be used to alleviate many diseases, and offer a viewpoint on the knowledge gaps that must be filled to render such a therapeutic approach a reality and, ideally, a common future practice in precision medicine.