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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.<\/jats:p>","DOI":"10.1038\/s41392-025-02523-1","type":"journal-article","created":{"date-parts":[[2025,12,15]],"date-time":"2025-12-15T03:44:45Z","timestamp":1765770285000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Selective depletion of tumor-associated SAMHD1 enhances chemotherapeutic efficacy and antitumor immune 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