Besides cytokines, molecules involved in the production of the immunosuppressive metabolite adenosine represent promising targets for BC therapy. novel therapeutic options that can revert the immunosuppressive Tyrphostin A1 activity of breast TME will be discussed. To this end, clinical trials assessing the efficacy of CAR-T and CAR-NK cells, cancer vaccination, immunogenic cell death-inducing chemotherapy, DNA methyl transferase and histone deacetylase inhibitors, cytokines or their inhibitors and other immunotherapies in breast cancer patients will be reviewed. The knowledge of the complex interplay that elapses between tumor and immune cells, and of the experimental therapies targeting it, would help to develop new combination treatments able to overcome tumor immune evasion mechanisms and optimize clinical benefit of current immunotherapies. (TGF-and studies indicate that MCs exhibit a pro-tumor activity through the promotion of lymphatic and blood vessel formation, tumor growth, and metastasis (26). On the other hand, Samoszuk et?al. exhibited that depletion of MCs Tyrphostin A1 with imatinib enhanced tumor growth in a murine model of BC, supporting MC anti-tumoral role (27). Another study associates MCs with a greater survival and favorable prognosis (28). Consistently, Rajput et?al. reported that in a cohort of 4.444 invasive BC patients with a long term follow-up, stromal MCs correlate with a good prognosis (29). M2-Like Tumor Associated Macrophages Macrophages are terminally differentiated myeloid cells which are responsible for the elimination of infectious brokers and the regulation of adaptive immunity. For many years, macrophage biological origin was attributed to bone marrow-derived progenitors and blood monocyte intermediates that differentiate into mature cells once seeded into organs (30). However, several genetic tracing data revealed that multiple macrophage populations develop from embryonic progenitors and are able to self-renew by local proliferation of mature, differentiated cells. Each tissue microenvironment has been demonstrated to influence macrophage morphological and functional characteristics (31). Based on their functional role, macrophages have been classified in two different subtypes: anti-tumoral M1-like and pro-tumoral M2-like polarized TAMs (32). In mice, both M1- and M2-like TAMs are characterized by the expression of markers such as CD11b, F4/80 and colony-stimulating factor-1 receptor (CSF-1R) and low levels of expression of the myeloid differentiation marker Gr1, whereas major histocompatibility complex (MHC) class II glycoproteins and CD206 are used to distinguish between M1- and M2-like TAMs, respectively. In humans, Tyrphostin A1 macrophages are identified by the expression of CD68, CD312, CD115, and other markers. However, it is important to note that TAM phenotypes are much more complex and categorizing them into binary says is not completely correct (33). Several data indicate that this pro-tumoral M2-like TAMs within the BCIM play pivotal roles Nrp2 in promoting tumorigenesis and metastasis formation both non-immune and immune related mechanisms. The nonimmune role of TAMs consists in the release of numerous angiogenic factors, such as vascular endothelial growth factor (VEGF), platelet-derived growth factor (PDGF), and basic fibroblast growth factor (bFGF), that stimulate angiogenesis within the tumor, as well as in the secretion of many Tyrphostin A1 signaling molecules, including Tyrphostin A1 EGF, matix metalloproteinases (MMPs), CCL2, CCL18, and macrophage (M)-CSF that consequently activate tumor cell epithelialCmesenchymal transition (EMT), invasion, and metastasis (34, 35). The pro-tumoral M2-like TAM infiltration contributes to establish an immunosuppressive microenvironment. For example, it has been reported that M2-like TAMs, through the secretion of TGF-derived from the CD4+ cells, but not from the CD8+ and NK cells, is responsible for the tumoricidal effects after Treg depletion in PyMT breast carcinomas (48). Anti-Tumor Immune Cells Tumor Infiltrating T cells TILs include all the cells with a lymphocytic nature infiltrating the tumor tissues. Of particular interest are cytotoxic (CD8+) and helper (CD4+) T-lymphocytes (49) that constitute an essential part of the adaptive immunity. CD8+ T-lymphocytes are the major effector cells involved in tumor elimination.