Li Jiabing, Zhang Shuang, Wang Baohui, Dai Yuting, Wu Jiale, Liu Dianjia, Liang Ying, Xiao Shujun, Wang Zhengyuan, Wu Jiaqi, Zheng Derun, Chen Xueqin, Shi Fangfang, Tan Kai, Ding Xianting, Song Huaxin, Zhang Sujiang, Lu Min
Shanghai Institute of Hematology, State Key Laboratory of Medical Genomics, National Research Center for Translational Medicine (Shanghai), Ruijin Hospital affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China.
State Key Laboratory of Systems Medicine for Cancer, Institute for Personalized Medicine and Med-X, Institute School of Biomedical Engineering Research, Shanghai Jiao Tong University, Shanghai, China.
Cell Rep Med. 2025 Mar 18;6(3):101976. doi: 10.1016/j.xcrm.2025.101976. Epub 2025 Feb 21.
Tumor suppressor p53 is the most frequently mutated protein in cancer, possessing untapped immune-modulating capabilities in anticancer treatment. Here, we investigate the efficacy and underlying mechanisms of pharmacological reactivation of mutant p53 in treating spontaneous tumors in mice. In the p53 R279W (equivalent to the human hotspot R282W) mouse model developing spontaneous tumors, arsenic trioxide (ATO) treatment through drinking water significantly prolongs the survival of mice, dependent on p53-R279W reactivation. Transient regressions of spontaneous T-lymphomas are observed in 70% of the ATO-treated mice, accompanied by interferon (IFN) response. In allograft models, the tumor-suppressive effect of reactivated p53-R279W is detectably reduced in both immunodeficient Rag1 and CD8 T cell-depleted mice. ATO also activates the IFN pathway in human cancer cells harboring various p53 mutations, as well as in primary samples derived from the p53-mutant patient treated with ATO. Together, p53 could serve as an alternative therapeutic target for the development of immunotherapies.
肿瘤抑制蛋白p53是癌症中最常发生突变的蛋白，在抗癌治疗中具有尚未开发的免疫调节能力。在此，我们研究了突变型p53的药理学再激活在治疗小鼠自发性肿瘤中的疗效及潜在机制。在发生自发性肿瘤的p53 R279W（等同于人类热点突变R282W）小鼠模型中，通过饮水给予三氧化二砷（ATO）治疗可显著延长小鼠生存期，这依赖于p53-R279W的再激活。在70%接受ATO治疗的小鼠中观察到自发性T淋巴瘤的短暂消退，并伴有干扰素（IFN）反应。在同种异体移植模型中，在免疫缺陷的Rag1和CD8 T细胞耗竭的小鼠中，再激活的p53-R279W的肿瘤抑制作用均明显降低。ATO还可激活携带各种p53突变的人类癌细胞以及来自接受ATO治疗的p53突变患者的原代样本中的IFN通路。总之，p53可作为免疫疗法开发的替代治疗靶点。
