整合素αv（ITGAV，CD51）被认为是肿瘤进展的多个阶段的重要组成部分。然而，针对表面CD51的特异性抑制剂cilengitide的临床失败暗示了CD51促进肿瘤进展的尚未知机制的重要性。在本研究中，我们使用了几条肝细胞癌（HCC）细胞系和小鼠肝癌细胞系。为了研究CD51在HCC进展中的作用，我们使用了3D侵袭分析、体内生物发光成像等方法。我们使用了periostin基因敲除转基因小鼠，揭示了肿瘤微环境对CD51裂解的作用。此外，我们使用了多种与临床相关的HCC模型，包括患者来源的器官样和异种移植等，来评估治疗效果。我们发现CD51能够经过γ-分泌酶的跨膜裂解来产生一个功能性的细胞内结构域（CD51-ICD）。裂解的CD51-ICD通过促进氧化磷酸化（OXPHOS）相关基因的转录来促进HCC的侵袭和转移。此外，我们确定了癌相关成纤维细胞（CAF）来源的periostin为CD51裂解的主要驱动因素。最后，我们显示在补充γ-分泌酶抑制剂LY3039478的情况下，cilengitide治疗在患者来源的异种移植（PDX）和小鼠异种移植模型中均显著改善。总之，我们揭示了CD51在HCC进展中的先前未认识到的作用机制，揭示了cilengitide治疗失败的潜在原因，并支持了临床上联合靶向CD51的治疗的转化前景。

Integrin αv (ITGAV, CD51) is regarded as a key component in multiple stages of tumor progression. However, the clinical failure of cilengitide, a specific inhibitor targeting surface CD51, suggests the importance of yet-unknown mechanisms by which CD51 promotes tumor progression.In this study, we used several hepatocellular carcinoma (HCC) cell lines and murine hepatoma cell lines. To investigate the role of CD51 on HCC progression, we used 3D invasion assay, in vivo bioluminescence imaging, etc. We used periostin-knockout transgenic mice to uncover the role of tumor microenvironment on CD51 cleavage. Moreover, we used several clinical-relevant HCC models, including patient-derived organoids, patient-derived xenografts etc, to evaluate the therapeutic efficacy.We found that CD51 could undergo transmembrane cleavage by γ-secretase to produce a functional intracellular domain (CD51-ICD). The cleaved CD51-ICD facilitated HCC invasion and metastasis by promoting the transcription of oxidative phosphorylation (OXPHOS)-related genes. Furthermore, we identified cancer-associated fibroblast (CAF)-derived periostin as the major driver for CD51 cleavage. Lastly, we showed that cilengitide-based therapy displayed a dramatic improvement in both patient-derived xenograft (PDX) and mouse xenograft models when supplemented with the γ-secretase inhibitor, LY3039478.To sum up, we revealed previously unrecognized action mechanisms of CD51 on HCC progression and uncovered the underlying cause of cilengitide treatment failure and supported the translational prospects of combined CD51-targeted therapy in the clinic.Integrin αv (CD51) is a widely recognized pro-tumoral molecule that plays a crucial role in various stages of tumor progression, making it a promising therapeutic target. However, despite early promising results, cilengitide, a specific antagonist of CD51, surprisingly failed in the phase 3 clinical trial. This prompted further investigation into the underlying mechanisms. This study reveals that the γ-secretase complex directly cleaves CD51 to produce an intracellular domain (CD51-ICD), which functions as a pro-tumoral transcriptional regulator and can bypass the inhibitory effects of cilengitide by entering the nucleus. Furthermore, the localization of CD51 in the nucleus is significantly associated with the prognosis of patients with HCC. These findings provide a theoretical basis for re-evaluating cilengitide in clinical settings and highlight the importance of identifying a more precise patient subpopulation for future clinical trials targeting CD51.Copyright © 2023. Published by Elsevier B.V.