免疫检查点阻断 (ICB) 的治疗潜力涵盖多种癌症；然而，其治疗肝细胞癌 (HCC) 的有效性经常受到固有耐药性和发展性耐药性的影响。本研究探讨了安罗替尼（一种广谱酪氨酸激酶抑制剂）与程序性死亡 1 (PD-1) 阻断剂相结合的有效性为治疗 HCC 的更有效策略提供了机制见解。使用患者来源的器官型组织球体和原位 HCC 小鼠模型，我们评估了安罗替尼联合 PD-1 阻断的有效性。使用飞行时间质谱流式细胞仪、RNA 测序和蛋白质组学跨细胞系、小鼠模型和 HCC 患者样本评估对肿瘤免疫微环境和潜在机制的影响。安罗替尼与抗 PD-1 抗体的组合增强临床前模型中针对 HCC 的免疫反应。安罗替尼通过 VEGFR2/AKT/HIF-1α 信号轴显着抑制转铁蛋白受体 (TFRC) 的表达。 CD8 T 细胞浸润到肿瘤微环境与 TFRC 的低表达相关。安罗替尼还增加了趋化因子 CXCL14 的水平，这对于吸引 CD8 T 细胞至关重要。 CXCL14 作为 TFRC 的下游效应子出现，在 TFRC 沉默后表现出表达升高。重要的是，低 TFRC 表达还与 HCC 患者更好的预后、对联合治疗的敏感性增强以及对抗 PD-1 治疗的良好反应相关。我们的研究结果强调了安罗替尼增强抗 PD-1 疗效的潜力通过靶向 TFRC 并增强 CXCL14 介导的 CD8 T 细胞浸润来治疗 HCC。这项研究有助于开发新的 HCC 治疗策略，强调精准医学在肿瘤学中的作用。安罗替尼和抗 PD-1 免疫疗法在 HCC 临床前模型中证明了协同作用。安罗替尼通过 VEGFR2/AKT/HIF-1α 通路抑制 TFRC 表达。通过抑制 TFRC 上调 CXCL14 可促进 CD8 T 细胞募集。 TFRC 成为评估晚期 HCC 患者预后和预测抗 PD-1 疗法反应的潜在生物标志物。© 2024 作者。约翰·威利出版的《临床与转化医学》

The therapeutic potential of immune checkpoint blockade (ICB) extends across various cancers; however, its effectiveness in treating hepatocellular carcinoma (HCC) is frequently curtailed by both inherent and developed resistance.This research explored the effectiveness of integrating anlotinib (a broad-spectrum tyrosine kinase inhibitor) with programmed death-1 (PD-1) blockade and offers mechanistic insights into more effective strategies for treating HCC.Using patient-derived organotypic tissue spheroids and orthotopic HCC mouse models, we assessed the effectiveness of anlotinib combined with PD-1 blockade. The impact on the tumour immune microenvironment and underlying mechanisms were assessed using time-of-flight mass cytometry, RNA sequencing, and proteomics across cell lines, mouse models, and HCC patient samples.The combination of anlotinib with an anti-PD-1 antibody enhanced the immune response against HCC in preclinical models. Anlotinib remarkably suppressed the expression of transferrin receptor (TFRC) via the VEGFR2/AKT/HIF-1α signaling axis. CD8+ T-cell infiltration into the tumour microenvironment correlated with low expression of TFRC. Anlotinib additionally increased the levels of the chemokine CXCL14, crucial for attracting CD8+ T cells. CXCL14 emerged as a downstream effector of TFRC, exhibiting elevated expression following the silencing of TFRC. Importantly, low TFRC expression was also associated with a better prognosis, enhanced sensitivity to combination therapy, and a favourable response to anti-PD-1 therapy in patients with HCC.Our findings highlight anlotinib's potential to augment the efficacy of anti-PD-1 immunotherapy in HCC by targeting TFRC and enhancing CXCL14-mediated CD8+ T-cell infiltration. This study contributes to developing novel therapeutic strategies for HCC, emphasizing the role of precision medicine in oncology.Synergistic effects of anlotinib and anti-PD-1 immunotherapy demonstrated in HCC preclinical models. Anlotinib inhibits TFRC expression via the VEGFR2/AKT/HIF-1α pathway. CXCL14 upregulation via TFRC suppression boosts CD8+ T-cell recruitment. TFRC emerges as a potential biomarker for evaluating prognosis and predicting response to anti-PD-1-based therapies in advanced HCC patients.© 2024 The Author(s). Clinical and Translational Medicine published by John Wiley & Sons Australia, Ltd on behalf of Shanghai Institute of Clinical Bioinformatics.