在一项Ⅱ期试验（CA209-678）中，放射性树脂微球-（钇-90）树脂微球联合奈伐单抗治疗晚期肝细胞癌（HCC）的治疗方案显示出了30.6%的有望反应率。然而，该治疗方案的反应机制和相关生物标志物仍然未知。通过采集治疗前和治疗过程中的样本，我们对来自该试验的33名患者的组织和血液样本进行了多模式分析，并研究了与有利反应相关的分子变化。我们发现，在反应者中，肿瘤突变负荷更高，NCOR1基因突变和干扰素γ通路的表达更高出现的频率更高。与此同时，非反应者倾向于富集一个新型的亚洲特异性转录亚型（Kaya_P2），该亚型具有高频率的染色体16缺失和上调的细胞周期通路。令人惊讶的是，与其他癌症类型不同，我们没有观察到T细胞群体与治疗反应之间的任何关联，但反应者的肿瘤中具有更高比例的CXCL9+/CXCR3+巨噬细胞。此外，在之前的免疫疗法试验中发现的生物标志物在当前人群中不具有预测能力，这表明将与差异性反应相关的独特分子环境景观存在。本研究揭示了与新治疗方案不同反应的广泛分子变化，并指出了在晚期HCC患者中利用联合治疗的新方向。 © 作者(或其雇主) 2023 授权在CC BY-NC下重复使用。不进行商业复用。参见权限和许可。由BMJ出版。

Combination therapy with radioembolization (yttrium-90)-resin microspheres) followed by nivolumab has shown a promising response rate of 30.6% in a Phase II trial (CA209-678) for advanced hepatocellular carcinoma (HCC); however, the response mechanisms and relevant biomarkers remain unknown.By collecting both pretreatment and on-treatment samples, we performed multimodal profiling of tissue and blood samples and investigated molecular changes associated with favorable responses in 33 patients from the trial.We found that higher tumor mutation burden, NCOR1 mutations and higher expression of interferon gamma pathways occurred more frequently in responders. Meanwhile, non-responders tended to be enriched for a novel Asian-specific transcriptomic subtype (Kaya_P2) with a high frequency of chromosome 16 deletions and upregulated cell cycle pathways. Strikingly, unlike other cancer types, we did not observe any association between T-cell populations and treatment response, but tumors from responders had a higher proportion of CXCL9+/CXCR3+ macrophages. Moreover, biomarkers discovered in previous immunotherapy trials were not predictive in the current cohort, suggesting a distinctive molecular landscape associated with differential responses to the combination therapy.This study unraveled extensive molecular changes underlying distinctive responses to the novel treatment and pinpointed new directions for harnessing combination therapy in patients with advanced HCC.© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.