Macrophages are key components of the tumor microenvironment, derived from blood monocytes and playing a critical role in cancer development. Tumor-associated macrophages (TAMs) can promote tumor growth, invasion, and metastasis by regulating programmed cell death ligand 1 (PD-L1) expression and interacting with other immune cells. However, when activated properly, macrophages can also exert anti-tumor effects by enhancing phagocytosis and cytotoxicity. TAMs are associated with poor prognosis and drug resistance in immunotherapy, making them attractive targets for combined therapy. Targeting TAMs with immunotherapy has shown promise in overcoming drug resistance and improving cancer treatment outcomes. This review discusses recent findings on the role of macrophages in tumor development, metastasis, and immunotherapy. It focuses on macrophage-centered therapies, including strategies to deplete and reprogram TAMs, which may enhance the efficacy of tumor immunotherapy. Macrophages can be classified into M1 (classically activated) and M2 (alternatively activated) types, with M1 macrophages promoting anti-tumor responses and M2 macrophages supporting tumor growth. TAMs are primarily M2 in the tumor microenvironment and can promote tumor progression by suppressing immune responses, inducing angiogenesis, and supporting cancer stem cells. The PD-1/PD-L1 pathway is abnormally activated in various cancers, and anti-PD-1/PD-L1 immunotherapy has shown promise in clinical trials. However, its efficacy is limited in some patients, and TAMs can regulate PD-L1 expression, contributing to resistance. Targeting TAMs in combination with anti-PD-1 therapy may enhance treatment outcomes by repolarizing macrophages and improving the tumor microenvironment. Current strategies for targeting macrophages include depletion and reprogramming. Depletion methods, such as inhibiting the CSF1/CSF1R signaling pathway, can reduce TAMs and improve immune responses. Reprogramming strategies, such as using HDAC inhibitors or PI3K pathway inhibitors, can enhance macrophage antitumor functions. CAR-macrophages, which are engineered to express chimeric antigen receptors, show potential in targeting solid tumors. Combining macrophage-targeting therapies with immunotherapy may overcome drug resistance and improve cancer treatment. However, further research is needed to fully understand the mechanisms and optimize these approaches for clinical application. The role of macrophages in cancer immunotherapy is a promising area of research with significant potential for future treatment strategies.Macrophages are key components of the tumor microenvironment, derived from blood monocytes and playing a critical role in cancer development. Tumor-associated macrophages (TAMs) can promote tumor growth, invasion, and metastasis by regulating programmed cell death ligand 1 (PD-L1) expression and interacting with other immune cells. However, when activated properly, macrophages can also exert anti-tumor effects by enhancing phagocytosis and cytotoxicity. TAMs are associated with poor prognosis and drug resistance in immunotherapy, making them attractive targets for combined therapy. Targeting TAMs with immunotherapy has shown promise in overcoming drug resistance and improving cancer treatment outcomes. This review discusses recent findings on the role of macrophages in tumor development, metastasis, and immunotherapy. It focuses on macrophage-centered therapies, including strategies to deplete and reprogram TAMs, which may enhance the efficacy of tumor immunotherapy. Macrophages can be classified into M1 (classically activated) and M2 (alternatively activated) types, with M1 macrophages promoting anti-tumor responses and M2 macrophages supporting tumor growth. TAMs are primarily M2 in the tumor microenvironment and can promote tumor progression by suppressing immune responses, inducing angiogenesis, and supporting cancer stem cells. The PD-1/PD-L1 pathway is abnormally activated in various cancers, and anti-PD-1/PD-L1 immunotherapy has shown promise in clinical trials. However, its efficacy is limited in some patients, and TAMs can regulate PD-L1 expression, contributing to resistance. Targeting TAMs in combination with anti-PD-1 therapy may enhance treatment outcomes by repolarizing macrophages and improving the tumor microenvironment. Current strategies for targeting macrophages include depletion and reprogramming. Depletion methods, such as inhibiting the CSF1/CSF1R signaling pathway, can reduce TAMs and improve immune responses. Reprogramming strategies, such as using HDAC inhibitors or PI3K pathway inhibitors, can enhance macrophage antitumor functions. CAR-macrophages, which are engineered to express chimeric antigen receptors, show potential in targeting solid tumors. Combining macrophage-targeting therapies with immunotherapy may overcome drug resistance and improve cancer treatment. However, further research is needed to fully understand the mechanisms and optimize these approaches for clinical application. The role of macrophages in cancer immunotherapy is a promising area of research with significant potential for future treatment strategies.