Selective depletion of tumor-associated SAMHD1 enhances chemotherapeutic efficacy and antitumor immune responses

SAMHD1 is a human deoxyribonucleoside triphosphatase (dNTPase) known for its role as a restriction factor that targets a wide spectrum of viruses, its involvement in autoimmune disease Aicardi-Goutières syndrome (AGS), and its participation in innate immune regulation. The role of SAMHD1 in cancer, particularly its contribution to drug resistance, has gained increasing attention in recent years. One significant scientific challenge is how to inhibit SAMHD1 function in tumor cells while preserving its function in normal primary cells. Herein, we identified that increased SAMHD1 expression levels correlate with poor prognosis across multiple cancer types, and that SAMHD1 is upregulated in a variety of tumors. Through proteomic analysis and drug screening, we identified a promising strategy for selectively depleting tumor-associated SAMHD1 while minimizing its impact on SAMHD1 expression in key normal cell types. Our approach effectively enhanced tumor cytotoxicity when combined with multiple chemotherapeutic agents and suppressed tumor growth in vivo. Moreover, selective depletion of tumor-associated SAMHD1 activated innate immune responses, leading to enhanced tumor cell killing by immune cells. Collectively, these findings suggest that targeting tumor-specific SAMHD1 represents a novel and promising therapeutic strategy for cancers characterized by elevated SAMHD1 expression, offering potential for improved treatment outcomes in cancer patients with high SAMHD1 expression.

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Publication Details

Journal
Signal Transduction and Targeted Therapy
Published
2025-12-15
DOI
https://doi.org/10.1038/s41392-025-02523-1
Primary Topic
interferon and immune responses
Type
article
Field-Weighted Citation Impact
0.00

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article

Selective depletion of tumor-associated SAMHD1 enhances chemotherapeutic efficacy and antitumor immune responses

Cang Li, Jing Sun, Dingbo Huang, Juan Du et al.
Signal Transduction and Targeted Therapy
interferon and immune responses
article

Selective depletion of tumor-associated SAMHD1 enhances chemotherapeutic efficacy and antitumor immune responses

Cang Li, Jing Sun, Dingbo Huang, Juan Du, Jie Yang, X R Zhang, Fei Xu, Songdi Wang, Runxin Ye, Ran Zhu, Jiaming Su, Xiaoyi Hu, Fengyan Xia, Zhongdao Wu, Yifei Shi, Weiming Yang, Shuang-Shuang Lyu, Yajuan Rui, Wanyu Li, Zhengguo Zhang, Rongzhen Xu, Wei Wei, Xiaoguang Wang, Zheng Wang, Ke Zhao, Jian Xu, Hongkun Zhou, Yu Huang, Qingfeng Yu, Xiao‐Fang Yu
article en

Abstract

SAMHD1 is a human deoxyribonucleoside triphosphatase (dNTPase) known for its role as a restriction factor that targets a wide spectrum of viruses, its involvement in autoimmune disease Aicardi-Goutières syndrome (AGS), and its participation in innate immune regulation. The role of SAMHD1 in cancer, particularly its contribution to drug resistance, has gained increasing attention in recent years. One significant scientific challenge is how to inhibit SAMHD1 function in tumor cells while preserving its function in normal primary cells. Herein, we identified that increased SAMHD1 expression levels correlate with poor prognosis across multiple cancer types, and that SAMHD1 is upregulated in a variety of tumors. Through proteomic analysis and drug screening, we identified a promising strategy for selectively depleting tumor-associated SAMHD1 while minimizing its impact on SAMHD1 expression in key normal cell types. Our approach effectively enhanced tumor cytotoxicity when combined with multiple chemotherapeutic agents and suppressed tumor growth in vivo. Moreover, selective depletion of tumor-associated SAMHD1 activated innate immune responses, leading to enhanced tumor cell killing by immune cells. Collectively, these findings suggest that targeting tumor-specific SAMHD1 represents a novel and promising therapeutic strategy for cancers characterized by elevated SAMHD1 expression, offering potential for improved treatment outcomes in cancer patients with high SAMHD1 expression.

Signal Transduction and Targeted TherapyVol. 10(1)
Zhejiang Chinese Medical University (CN), Johns Hopkins University (US), Zhejiang University of Science and Technology (CN), Jilin University (CN), Yale University (US), Jiaxing University (CN), Zhejiang Cancer Hospital (CN), First Hospital of Jilin University (CN), First Hospital of Jiaxing (CN), Second Affiliated Hospital of Zhejiang University (CN), Zhejiang University (CN)
National Natural Science Foundation of China, Fundamental Research Funds for the Central Universities
Openalex Percentile: Top 54%
interferon and immune responses
DOIOpen Access PDFOpenAlex
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