AbstractMacrophages 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.