Loss of fragile site-associated tumor suppressor promotes antitumor immunity via macrophage polarization

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作者：Zhang Lijuan, Zhang Kai, Zhang Jieyou, Zhu Jinrong, Xi Qing, Wang Huafeng, Zhang Zimu, Cheng Yingnan, Yang Guangze, Liu Hongkun, Guo Xiangdong, Zhou Dongmei, Xue Zhenyi, Li Yan, Zhang Qi, Da Yurong, Liu Li, Yin Zhinan, Yao Zhi, Zhang Rongxin
期刊：Nature Communications
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Common fragile sites (CFSs) are specific breakage-prone genomic regions and are present frequently in cancer cells. The (E2-independent) E3 ubiquitin-conjugating enzyme FATS (fragile site-associated tumor suppressor) has antitumor activity in cancer cells, but the function of FATS in immune cells is unknown. Here, we report a function of FATS in tumor development via regulation of tumor immunity. Fats^-/- mice show reduced subcutaneous B16 melanoma and H7 pancreatic tumor growth compared with WT controls. The reduced tumor growth in Fats^-/- mice is macrophage dependent and is associated with a phenotypic shift of macrophages within the tumor from tumor-promoting M2-like to antitumor M1-like macrophages. In addition, FATS deficiency promotes M1 polarization by stimulating and prolonging NF-κB activation by disrupting NF-κB/IκBα negative feedback loops and indirectly enhances both CD4⁺ T helper type 1 (Th1) and cytotoxic T lymphocyte (CTL) adaptive immune responses to promote tumor regression. Notably, transfer of Fats^-/- macrophages protects mice against B16 melanoma. Together, these data suggest that FATS functions as an immune regulator and is a potential target in cancer immunotherapy.