在早期乳腺癌患者中，存在一种仍未满足的临床需求，即在新辅助化疗(NACT)后未获得完全病理学反应的病例中缺乏经过验证的代用生物标志物。本文中，我们描述并验证了 SAMHD1 表达作为预后生物标志物在体内和体外残留病变中的应用。我们评估了在接受 NACT 治疗的早期乳腺癌患者（II-III 期）的临床队列中的 SAMHD1 表达。我们采用包括肿瘤和免疫细胞的异种细胞三维培养模型来研究 SAMHD1 消耗的分子机制，包括全转录组分析、免疫浸润能力以及后续对失调的免疫信号通路的划定。在乳腺癌患者残留病变的术后 NACT 肿瘤活检中，SAMHD1 表达与复发风险增加和较高的 Ki67 水平相关。生存分析显示，表达 SAMHD1 的肿瘤的进展时间和总生存期比 SAMHD1 阴性病例短，表明 SAMHD1 表达是乳腺癌中一个相关的预后因子。SAMHD1 消耗肿瘤的全转录组分析确定了 IL-12 信号通路的下调作为决定乳腺癌预后的分子机制。SAMHD1 消耗后的白细胞介素信号传导减少引起了 3D 异种细胞体外培养模型中免疫细胞浸润能力的变化，证实了 SAMHD1 作为调节乳腺癌预后的因子，通过引发免疫应答和肿瘤微环境的变化。SAMHD1 表达是早期乳腺癌中的一种新的预后生物标志物，影响免疫介导的信号传导，不同调节炎症性肿瘤内部反应。以上所述，由本文作者提供，2023年。

The lack of validated surrogate biomarkers is still an unmet clinical need in the management of early breast cancer cases that do not achieve complete pathological response after neoadjuvant chemotherapy (NACT). Here, we describe and validate the use of SAMHD1 expression as a prognostic biomarker in residual disease in vivo and in vitro.SAMHD1 expression was evaluated in a clinical cohort of early breast cancer patients with stage II-III treated with NACT. Heterotypic 3D cultures including tumor and immune cells were used to investigate the molecular mechanisms responsible of SAMHD1 depletion through whole transcriptomic profiling, immune infiltration capacity and subsequent delineation of dysregulated immune signaling pathways.SAMHD1 expression was associated to increased risk of recurrence and higher Ki67 levels in post-NACT tumor biopsies of breast cancer patients with residual disease. Survival analysis showed that SAMHD1-expressing tumors presented shorter time-to-progression and overall survival than SAMHD1 negative cases, suggesting that SAMHD1 expression is a relevant prognostic factor in breast cancer. Whole-transcriptomic profiling of SAMHD1-depleted tumors identified downregulation of IL-12 signaling pathway as the molecular mechanism determining breast cancer prognosis. The reduced interleukin signaling upon SAMHD1 depletion induced changes in immune cell infiltration capacity in 3D heterotypic in vitro culture models, confirming the role of the SAMHD1 as a regulator of breast cancer prognosis through the induction of changes in immune response and tumor microenvironment.SAMHD1 expression is a novel prognostic biomarker in early breast cancer that impacts immune-mediated signaling and differentially regulates inflammatory intra-tumoral response.© 2023. The Author(s).