Identifying the cellular and molecular suppressors of the immune response against tumors is a popular topic in the field of tumor immunology that will provide new targets for the cancer immunotherapy. Suppressing the suppressor is a very attractive approach to enhancing the anti-tumor immune response by reversing the immunosuppression or blocking immune escape in the late stages of cancer progression. It is well known that tumors, especially at the late stage of development, can actively drive the generation of immunosuppressive or regulatory immune cell subtypes and can also induce the massive accumulation of tumor-promoting myeloid immune cells in the tumor microenvironment. For example, myeloid-derived suppressor cells, tumor-associated macrophages (TAMs) and regulatory T cells have been found to be the major tumor-promoting immune cells in the tumor microenvironment. 1 Although much work has been con ducted to identify the molecular mechanisms of the generation and accumulation of these types of tumor-promoting cells locally in the tumor microenvironment and systemically in the draining lymph nodes and other organs, the precise molecular mechanisms for their mobilization, differentiation, accumulation and function remain to be further investigated. Another key question in this field surrounds the difference and functional relationship between the migrating or recruited immune cells and the tissue-resident immune cells in the tumor microenvironment. Macrophages are a population of immune cells with a high degree of phenotypic and functional heterogeneity. Macrophages, which are widely distributed in all tissues, play a major role in the host innate immune response against infections; additionally, macrophages are well recognized for their roles in homeostasis, tissue repair and development. 2 In the last decade, there have been numerous reports about the relationship between macrophages and tumors. One of the major concerns in this field is the origin and function of TAMs. TAMs can enhance tumor cell proliferation, invasion and metastasis; stimulate angiogenesis; and inhibit the T cellmediated anti-tumor immune response, thus promoting tumor progression. 3, 4 Much clinical data show that more accumulation of TAMs in the tumor tissue indicates a poor prognosis for cancer patients. 5 However, there are contradicting reports about the cellular origin of TAMs accumulated in the tumor microenvironment and the identification of the master molecule responsible for TAM differentiation from their precursors. In a recent issue of Science, Franklin et al. 6 reported that TAMs are phenotypically and functionally different from the traditional M2 TAMs in the mouse model of mammary cancer; the group reported that TAMs are differentiated from CCR2+ inflammatory monocytes and that their differentiation depends on the Notch signaling pathway via the transcription factor RBPJ (Figure 1). These new findings not only enrich our understanding of the origin and function of TAMs, but also propose new pathways for the differentiation of TAMs, thus providing new clues for developing strategies for cancer immunotherapy. As an important type of immune cells in the tumor microenvironment, macrophages have been demonstrated to be important in tumor progression, depending on the stage of tumor development and the tumor type. 7 Generally, TAMs are accepted to promote tumor progression via different mechanisms. Macrophages are a heterogeneous cell population that can be conventionally divided into two subgroups: M1 and M2. M1-type macrophages, which are classically activated, play important roles in the innate …