Dai Panpan, Sun Yishuang, Huang Zhengrong, Liu Yu-Tong, Gao Minling, Liu Hai-Ming, Shi Jie, He Chuan, Xiang Bolin, Yao Yingmeng, Yu Haisheng, Xu Gaoshan, Kong Lijun, Xiao Xiangling, Wang Xiyong, Zhang Xue, Xiong Wenjun, Hu Jing, Lin Dandan, Zhong Bo, Chen Gang, Gong Yan, Xie Conghua, Zhang Jinfang
Department of Radiation and Medical Oncology, Medical Research Institute, Frontier Science Center of Immunology and Metabolism, Hubei Key Laboratory of Tumor Biological Behavior, Hubei Provincial Clinical Research Center for Cancer, Zhongnan Hospital of Wuhan University, Wuhan University, Wuhan, China.
State Key Laboratory of Metabolism and Regulation in Complex Organisms, College of Life Sciences, Taikang Center for Life and Medical Sciences, Wuhan University, Wuhan, China.
Nat Commun. 2025 May 16;16(1):4564. doi: 10.1038/s41467-025-59621-5.
The CD47/SIRPα axis conveys a 'don't eat me' signal, thereby thwarting the phagocytic clearance of tumor cells. Although blocking antibodies targeting CD47 have demonstrated promising anti-tumor effects in preclinical models, clinical trials involving human cancer patients have not yielded ideal results. Exploring the regulatory mechanisms of CD47 is imperative for devising more efficacious combinational therapies. Here, we report that inhibiting USP2 prompts CD47 degradation and reshapes the tumor microenvironment (TME), thereby enhancing anti-PD-1 immunotherapy. Mechanistically, USP2 interacts with CD47, stabilizing it through deubiquitination. USP2 inhibition destabilizes CD47, thereby boosting macrophage phagocytosis. Single-cell RNA sequencing shows USP2 inhibition reprograms TME, evidenced by increasing M1 macrophages and CD8 T cells while reducing M2 macrophages. Combining ML364 with anti-PD-1 reduces tumor burden in mouse models. Clinically, low USP2 expression predicts a better response to anti-PD-1 treatment. Our findings uncover the regulatory mechanism of CD47 by USP2 and targeting this axis boosts anti-tumor immunity.
CD47/SIRPα轴传递一种“别吃我”信号，从而阻碍肿瘤细胞的吞噬清除。尽管靶向CD47的阻断抗体在临床前模型中已显示出有前景的抗肿瘤作用，但涉及人类癌症患者的临床试验尚未产生理想结果。探索CD47的调控机制对于设计更有效的联合疗法至关重要。在此，我们报告抑制USP2可促使CD47降解并重塑肿瘤微环境（TME），从而增强抗PD-1免疫疗法。机制上，USP2与CD47相互作用，通过去泛素化使其稳定。USP2抑制使CD47不稳定，从而增强巨噬细胞吞噬作用。单细胞RNA测序显示USP2抑制可重编程TME，表现为M1巨噬细胞和CD8 T细胞增加而M2巨噬细胞减少。在小鼠模型中，将ML364与抗PD-1联合使用可减轻肿瘤负担。在临床上，低USP2表达预示对抗PD-1治疗有更好反应。我们的研究结果揭示了USP2对CD47的调控机制，靶向该轴可增强抗肿瘤免疫力。
