USP2 inhibition unleashes CD47-restrained phagocytosis and enhances anti-tumor immunity

Panpan Dai, Yishuang Sun, Zhengrong Huang, Yu-Tong Liu, Minling Gao, Hai-Ming Liu, Jie Shi, Chuan He, Bolin Xiang, Yingmeng Yao, Haisheng Yu, Gaoshan Xu, Lijun Kong, Xiangling Xiao, Xiyong Wang, Xue Zhang, Wenjun Xiong, Jing Hu, Dandan Lin, Bo Zhong, Gang Chen (), Yan Gong (), Conghua Xie () and Jinfang Zhang ()
Additional contact information
Panpan Dai: Wuhan University
Yishuang Sun: Wuhan University
Zhengrong Huang: Zhongnan Hospital of Wuhan University
Yu-Tong Liu: Wuhan University
Minling Gao: Wuhan University
Hai-Ming Liu: Wuhan University
Jie Shi: Wuhan University
Chuan He: Wuhan University
Bolin Xiang: Wuhan University
Yingmeng Yao: Wuhan University
Haisheng Yu: Wuhan University
Gaoshan Xu: Wuhan University
Lijun Kong: Wuhan University
Xiangling Xiao: Wuhan University
Xiyong Wang: Wuhan University
Xue Zhang: Wuhan University
Wenjun Xiong: Wuhan University
Jing Hu: Wuhan University
Dandan Lin: Renmin Hospital of Wuhan University
Bo Zhong: Wuhan University
Gang Chen: Wuhan University
Yan Gong: Zhongnan Hospital of Wuhan University
Conghua Xie: Wuhan University
Jinfang Zhang: Wuhan University

Nature Communications, 2025, vol. 16, issue 1, 1-22

Abstract: Abstract 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.

Date: 2025
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DOI: 10.1038/s41467-025-59621-5

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