Macrophage polarity in cancer: A review

Macrophages are the most abundant cells within the tumor stroma displaying noticeable plasticity, which allows them to perform several functions within the tumor microenvironment. Tumor-associated macrophages commonly refer to an alternative M2 phenotype, exhibiting anti-inflammatory and pro-tumoral effects. M2 cells are highly versatile and multi-tasking cells that directly influence multiple steps in tumor development, including cancer cell survival, proliferation, stemness, and invasiveness along with angiogenesis and immunosuppression. M2 cells perform these functions through critical interactions with cells related to tumor progression, including Th2 cells, cancer-associated fibroblasts, cancer cells, regulatory T cells (Tregs), and myeloid-derived suppressor cells. M2 cells also have negative cross-talks with tumor suppressor cells, including cytotoxic T cells and natural killer cells. Programed death-1 (PD-1) is one of the key receptors expressed in M2 cells that, upon interaction with its ligand PD-L1, plays cardinal roles for induction of immune evasion in cancer cells. In addition, M2 cells can neutralize the effects of the pro-inflammatory and anti-tumor M1 phenotype. Classically activated M1 cells express high levels of major histocompatibility complex molecules, and the cells are strong killers of cancer cells. Therefore, orchestrating M2 reprogramming toward an M1 phenotype would offer a promising approach for reversing the fate of tumor and promoting cancer regression. Macrophage switching toward an anti-inflammatory M1 phenotype could be used as an adjuvant with other approaches, including radiotherapy and immune checkpoint blockades, such as anti-PD-L1/PD-1 strategies. Highlights Pro-and/or anti-tumor characteristics of macrophages are tightly influenced by inducers, modifiers, and effector signals. An inducer is a cell or a range of cells within the tumor microenvironment that triggers signal transduction. This is further needed to be modified for either amplification or harassment of the signals relied by an inducer. Hypoxic condition is an example of a modifier. Finally, the modified signal is needed to be influential on the target cell (here is macrophages). Treatment strategies must be aimed on this triangle of signal transduction. Among various cells implicated in M2-mediated cancer progression, cancer cells take the most important role having tight interactions with M2 cells. These interactions are bidirectional in which cancer cells induce M2 polarity that in turn promote malignant behavior in cancer cells, Cancer cells take crucial roles for activation of a vicious immunosuppressive triangle formed by M2 cells, Tregs and myeloid-derived suppressor cells, M2 reprogramming toward a M1 phenotype is a promising approach for improving the efficacy of anti-cancer therapies. M1 cells orchestrate Th1 responses, while M2 cells orchestrate Th2 responses.