Oura Kyoko, Morishita Asahiro, Tadokoro Tomoko, Fujita Koji, Tani Joji, Kobara Hideki
Department of Gastroenterology and Neurology, Faculty of Medicine, Kagawa University, 1750-1 Ikenobe, Miki, Kita 761-0793, Kagawa, Japan.
Int J Mol Sci. 2024 Dec 19;25(24):13590. doi: 10.3390/ijms252413590.
Systemic therapy for unresectable hepatocellular carcinoma (HCC) has progressed with the development of multiple kinases, such as vascular endothelial growth factor (VEGF) signaling, targeting cancer growth and angiogenesis. Additionally, the efficacy of sorafenib, regorafenib, lenvatinib, ramucirumab, and cabozantinib has been demonstrated in various clinical trials, and they are now widely used in clinical practice. Furthermore, the development of effective immune checkpoint inhibitors has progressed in systemic therapy for unresectable HCC, and atezolizumab + bevacizumab (atezo/bev) therapy and durvalumab + tremelimumab therapy are now recommended as first-line treatment. Atezo/bev therapy, which combines an anti-programmed cell death 1 ligand 1 antibody with an anti-VEGF antibody, is the first cancer immunotherapy to demonstrate efficacy against unresectable HCC. With the increasing popularity of these treatments, VEGF inhibition is attracting attention from the perspective of its anti-angiogenic effects and impact on the cancer-immune cycle. In this review, we outline the role of VEGF in the tumor immune microenvironment and cancer immune cycle in HCC and outline the potential immune regulatory mechanisms of VEGF. Furthermore, we consider the potential significance of the dual inhibition of angiogenesis and immune-related molecules by VEGF, and ultimately aim to clarify the latest treatment strategies that maximizes efficacy.
随着多种激酶的发展，如针对癌症生长和血管生成的血管内皮生长因子（VEGF）信号通路，不可切除肝细胞癌（HCC）的系统治疗取得了进展。此外，索拉非尼、瑞戈非尼、仑伐替尼、雷莫西尤单抗和卡博替尼的疗效已在各种临床试验中得到证实，目前它们已广泛应用于临床实践。此外，有效的免疫检查点抑制剂在不可切除HCC的系统治疗中也取得了进展，阿替利珠单抗+贝伐珠单抗（阿替利珠单抗/贝伐珠单抗）治疗和度伐鲁单抗+曲美木单抗治疗目前被推荐作为一线治疗。阿替利珠单抗/贝伐珠单抗治疗将抗程序性细胞死亡1配体1抗体与抗VEGF抗体联合使用，是首个证明对不可切除HCC有效的癌症免疫疗法。随着这些治疗方法的日益普及，VEGF抑制因其抗血管生成作用及其对癌症免疫循环的影响而受到关注。在本综述中，我们概述了VEGF在HCC肿瘤免疫微环境和癌症免疫循环中的作用，并概述了VEGF潜在的免疫调节机制。此外，我们考虑了VEGF对血管生成和免疫相关分子双重抑制的潜在意义，最终旨在阐明能使疗效最大化的最新治疗策略。
