Although immune checkpoint therapy has significantly improved the prognosis of patients with melanoma, urgent attention still needs to be paid to the low patient response rates and the challenges of precisely identifying patients before treatment. Therefore, it is crucial to investigate novel immunosuppressive mechanisms and targets in the tumor microenvironment in order to reverse tumor immune escape. In this study, we found that the cell cycle checkpoint Aurora kinase B (AURKB) suppressed the anti-tumor immune response, and its inhibitor, Tozasertib, effectively activated T lymphocyte cytokine release and anti-tumor immunity . Tozasertib significantly inhibited melanoma xenograft tumor growth by decreasing the number of inhibitory CD4 T cells in the tumors, which, in turn, activated CD8 T cells. Single-cell analysis revealed that AURKB suppressed anti-tumor immunity by increasing MIF-CD74/CXCR4 signaling between tumor cells and lymphocytes. Our study suggests that AURKB is a newly identified anti-tumor immunity suppressor, whose inhibitors may be developed as novel anti-tumor immunity drugs and may have synergistic anti-melanoma effects with immune checkpoint therapies.

中文翻译：

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Tozasertib 通过减少黑色素瘤中的调节性 T 细胞激活抗肿瘤免疫

尽管免疫检查点治疗显着改善了黑色素瘤患者的预后，但仍需要迫切关注患者反应率低以及治疗前精确识别患者的挑战。因此，研究肿瘤微环境中新的免疫抑制机制和靶点以逆转肿瘤免疫逃逸至关重要。在本研究中，我们发现细胞周期检查点极光激酶B（AURKB）抑制抗肿瘤免疫反应，其抑制剂Tozasertib有效激活T淋巴细胞细胞因子释放和抗肿瘤免疫。Tozasertib 通过减少肿瘤中抑制性 CD4 T 细胞的数量来显着抑制黑色素瘤异种移植肿瘤的生长，从而激活 CD8 T 细胞。单细胞分析表明，AURKB 通过增加肿瘤细胞和淋巴细胞之间的 MIF-CD74/CXCR4 信号传导来抑制抗肿瘤免疫。我们的研究表明AURKB是一种新发现的抗肿瘤免疫抑制剂，其抑制剂可能被开发为新型抗肿瘤免疫药物，并可能与免疫检查点疗法具有协同抗黑色素瘤作用。