靶向PD-1/PD-L1通路的免疫检查点抑制剂(ICIs)是晚期非小细胞肺癌(NSCLC)患者的主要治疗选择，而无法应用药物靶向的致癌基因改变的病例尤其如此。然而，仅有部分患者从这种治疗方式中受益。本研究通过分析浅度全基因组测序(sWGS)技术在血浆样本中的价值，以监测ICIs的疗效。我们利用sWGS技术分析了45位接受ICIs治疗的转移性NSCLC患者的细胞外DNA(cfDNA)样本，共获得150多个样本，在治疗启动前和治疗过程中的几个时间点进行样本收集。通过sWGS数据计算出肿瘤部分(TFx)和体细胞染色体数量变异(SCNAs)负荷，并将其与ICIs的疗效和临床特征相关联。基线TFx与骨和肝的转移病变相关，较高的TFx(≥10%)与ICIs的疗效相关。此外，在治疗样本中评估ICIs的疗效，能够更好地预测临床疗效，无论基线TFx水平如何。最后，对于那些SCNAs负荷可计算的患者，增加的负荷与ICIs治疗后的效益降低相关。因此，我们的数据表明，通过sWGS分析cfDNA可在成本效益的前提下，监测ICIs对TFx和SCNAs负荷等两个潜在生物标志物的效益，从而方便进行多次连续样本分析。需要更大的样本来建立其临床应用潜力。本文受版权保护。保留所有权利。

Immune checkpoint inhibitors (ICIs) targeting the PD-1/PD-L1 axis are the main therapeutic option for patients with advanced non-small cell lung cancer (NSCLC) without a druggable oncogenic alteration. Nevertheless, only a portion of patients benefit from this type of treatment. Here, we assessed the value of shallow whole-genome sequencing (sWGS) on plasma samples to monitor ICIs benefit. We applied sWGS on cell-free DNA (cfDNA) extracted from plasma samples of 45 patients with metastatic NSCLC treated with ICIs. Over 150 samples were obtained before ICIs treatment initiation and at several time points throughout treatment. From sWGS data, we computed the tumor fraction (TFx) and somatic copy number alterations (SCNAs) burden and associated them with ICIs benefit and clinical features. TFx at baseline correlated with metastatic lesions at the bone and the liver, and high TFx (≥10%) associated with ICIs benefit. Moreover, its assessment in on-treatment samples was able to better predict clinical efficacy, regardless of the TFx levels at baseline. Finally, for a subset of patients for whom SCNAs burden could be computed, increased burden correlated with diminished benefit following ICIs treatment. Thus, our data indicate that the analysis of cfDNA by sWGS enables the monitoring of two potential biomarkers-TFx and SCNAs burden-of ICIs benefit in a cost-effective manner, facilitating multiple serial-sample analyses. Larger cohorts will be needed to establish its clinical potential.This article is protected by copyright. All rights reserved.