SAMHD1, short for sterile α motif and HD domain-containing protein 1, is a major cellular deoxyribonucleoside triphosphate triphosphohydrolase (dNTPase). It balances the intracellular deoxynucleotide (dNTP) pool, playing a crucial role in various cellular processes such as DNA replication, repair, and innate immune responses [1]. Mutations in SAMHD1 are implicated in diseases like Aicardi-Goutières syndrome and various cancers, highlighting its biological importance. Genetic models, such as KO/CKO mouse models, are valuable tools for studying its functions.

In human cell lines, SAMHD1-depleted cells show that the protein promotes degradation of nascent DNA at stalled replication forks by stimulating MRE11 exonuclease activity. This activates the ATR-CHK1 checkpoint, allowing fork restart. Without SAMHD1, single-stranded DNA fragments from stalled forks accumulate in the cytosol, activating the cGAS-STING pathway and inducing pro-inflammatory type I interferons, suggesting its role in preventing chronic inflammation [2]. In diffuse large B-cell lymphoma (DLBCL), SAMHD1 deficiency induced STING expression, inhibited tumor growth, and promoted PANoptosis, enhancing the efficacy of PD-L1 blockade [3].

In conclusion, SAMHD1 is essential for maintaining dNTP pool balance, participating in DNA-related processes and immune regulation. Model-based research, especially through KO/CKO mouse models, has revealed its role in preventing chronic inflammation and in cancer-related processes like tumor growth and immune checkpoint blockade efficacy in DLBCL.