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However, there are two main challenges in successfully utilizing macrophages for immunotherapy. First, macrophage colony stimulating factor (MCSF) secreted by cancer cells binds to colony stimulating factor 1 receptor (CSF1\u2010R) on macrophages and in turn activates the downstream signaling pathway responsible for polarization of tumor\u2010associated macrophages (TAMs) to immunosuppressive M2 phenotype. Second, ligation of signal regulatory protein \u03b1 (SIRP\u03b1) expressed on myeloid cells to CD47, a transmembrane protein overexpressed on cancer cells, activates the Src homology region 2 (SH2) domain \u2010phosphatases SHP\u20101 and SHP\u20102 in macrophages. This results in activation of \u201ceat\u2010me\u2010not\u201d signaling pathway and inhibition of phagocytosis. Here, it is reported that self\u2010assembled dual\u2010inhibitor\u2010loaded nanoparticles (DNTs) target M2 macrophages and simultaneously inhibit CSF1R and SHP2 pathways. This results in efficient repolarization of M2 macrophages to an active M1 phenotype, and superior phagocytic capabilities as compared to individual drug treatments. Furthermore, suboptimal dose administration of DNTs in highly aggressive breast cancer and melanoma mouse models show enhanced anti\u2010tumor efficacy without any toxicity. These studies demonstrate that the concurrent inhibition of CSF1\u2010R and SHP2 signaling pathways for macrophage activation and phagocytosis enhancement could be an effective strategy for macrophage\u2010based immunotherapy.<\/jats:p>","DOI":"10.1002\/adma.201904364","type":"journal-article","created":{"date-parts":[[2019,10,29]],"date-time":"2019-10-29T04:02:20Z","timestamp":1572321740000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":160,"title":["CSF1R\u2010 and SHP2\u2010Inhibitor\u2010Loaded Nanoparticles Enhance Cytotoxic Activity and Phagocytosis in Tumor\u2010Associated Macrophages"],"prefix":"10.1002","volume":"31","author":[{"given":"Anujan","family":"Ramesh","sequence":"first","affiliation":[{"name":"Department of Chemical Engineering University of Massachusetts  Amherst MA 01003\u20109364 USA"},{"name":"Department of Biomedical Engineering University of Massachusetts  Amherst MA 01003\u20109364 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