Tumor macrophage functional heterogeneity can inform the development of novel cancer therapies

•Single cell transcriptomics and spatial profiling have revealed that tumor associated macrophages (TAMs) comprise multiple subtypes (molecularly), and harbor different functions within the tumor microenvironment (TME). This can depend on their spatial localization, tumor type, and disease stage.•Six major macrophage clusters might exist in tumors including: inflammatory macrophages (Inf-TAMs), angiogenic macrophages (Ang-TAMs), immune regulatory macrophages (Reg-TAMs), interferon mediated regulatory macrophages (Inf-Reg TAMs), immune stimulatory macrophages, and a CD169+ macrophage cluster whose distinct function remains an active area of investigation.•Putative therapies aiming to specifically target these functional classes of macrophages are actively being tested pre-clinically and might begin to show clinical impact. The aim is to block the immunosuppressive, inflammatory, or angiogenic activities of these macrophages. A deeper understanding of the molecular, spatial, and functional heterogeneity of tumor associated macrophages, within the local tumor microenvironment has driven the development of a new class of therapies directed against such diverse functional subsets. This is leading to impressive anti-tumor responses in preclinical models and is now being tested in patients when given as monotherapies or in combination with targeted and T cell-based immunotherapies. Macrophages represent a key component of the tumor microenvironment and are largely associated with poor prognosis. Therapeutic targeting of macrophages has historically focused on inhibiting their recruitment or reprogramming their phenotype from a pro-tumor (‘M2-like’) to an anti-tumor (‘M1-like’) one. Unfortunately, this approach has not provided clinical breakthroughs that have changed practice. Emerging studies utilizing single-cell RNA-sequencing and spatial transcriptomics have improved our understanding of the ontogeny, phenotype, and functional plasticity of macrophages. Overlaying the wealth of current information regarding macrophage molecular subtypes and functions has also identified novel therapeutic vulnerabilities that might drive better control of tumor associated macrophages. Here, we discuss the functional profiling of macrophages and provide an update of novel macrophage-targeted therapies in development. Macrophages represent a key component of the tumor microenvironment and are largely associated with poor prognosis. Therapeutic targeting of macrophages has histor