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Abstract Background Cell fusion (CF) is a normal biological process that plays major role in mammalian development and differentiation. Through CF, somatic cells acquire nuclear reprogramming and epigenetic modifications to form pluripotent hybrid cells, which constitute an efficient process of rapid evolution to generate hybrids with new genetic, phenotypic and functional properties at a rate exceeding that achievable by random mutagenesis. Experimental and clinical evidences indicate that CF occurs in solid tumors and contribute to cancer progression by generating progeny with metastatic features and resistance to oncologic treatments. Phosphatidylserine (PS) is a glycerophospholipid, recognized by CD36 receptor in macrophage to detect apoptotic cells. The PS-CD36 interaction is a crucial step in fusion between monocytes and tumor cells. The aim of this study is to investigate the impact of the PS-CD36 expression in macrophage–cancer cell fusion and in relation to ionizing radiation (IR). Methods GFP-labeled breast cancer MCF-7 cells and macrophages (differentiated monocyte cell line THP-1) were used in CF in vitro experiment with IR (figure 1). MCF-7/macrophage hybrids were generated by spontaneous CF, isolated by fluorescence activated cell sorting and confirmed by fluorescence microscopy. We treated the hybrids and their maternal cells (MCF-7 and macrophages) with IR (ɣ-irradiation, 0Gy, 2.5Gy and 5Gy). Anti-CD36 antibody, 40µg and 80µg, was used to block CD36 receptor. CF rate is based on the number of seeded macrophages, since they do not proliferate. The proportion of hybrids = (number of hybrids/number of seeded macrophages in same sample) x100. Results IR induces the exposure of PS (dose dependent) on MCF-7 cells, which was not found in macrophages. IR also induces significant expression of CD36 in THP-1 cells. CF was inhibited by blocking of CD36 receptor with anti-CD36 antibodies (figure 2). Conclusions IR induces macrophage-cancer cell fusion by stimulating the exposure of PS on MCF-7 cells and the expression of CD36 in macophages. CF and the generation of metastatic hybrids can be prevented by inhibiting the PS-CD36 interaction, a mechanism constituting an essential step in macrophage-cancer CF. Legal entity responsible for the study Ivan Shabo, Karolinska Institutet, Stockholm Sweden. Funding Swedish Society of Medicine. Disclosure All authors have declared no conflicts of interest.