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<p>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.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年12月15日

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  • Jing Sun,
  • Wenwen Zheng,
  • Zheng-Guo Zhang,
  • Hongkun Zhou,
  • Songdi Wang,
  • Dingbo Huang,
  • Xiao-Yi Hu,
  • Qing-Feng Yu,
  • Zhao-Xing Wu,
  • Yi-Fei Shi,
  • Runxin Ye,
  • Fengyan Xia,
  • Wangwei Li,
  • Shurui Lyu,
  • Yu Huang,
  • Xu-Zhao Zhang,
  • Fei Xu,
  • Ke Zhao,
  • Jie Yang,
  • Juan Du,
  • Jiaming Su,
  • Yajuan Rui,
  • Rongzhen Xu,
  • Wei-Ming Yang,
  • Cang Li,
  • Jia ling Xu,
  • Ruiyu Zhu,
  • Xiaoguang Wang,
  • Wei Wei,
  • Xiao-Fang Yu

摘要

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.