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肝细胞癌肿瘤微环境的免疫格局与分子治疗靶点

Immunological Landscape and Molecular Therapeutic Targets of the Tumor Microenvironment in Hepatocellular Carcinoma.

作者信息

Zarlashat Yusra, Ghaffar Abdul, Guerra Flora, Picca Anna

机构信息

Department of Biochemistry, Government College University Faisalabad, Faisalabad 38000, Pakistan.

Department of Biological and Environmental Sciences and Technologies (DiSTeBA), University of Salento, 73100 Lecce, Italy.

出版信息

Int J Mol Sci. 2025 Aug 13;26(16):7836. doi: 10.3390/ijms26167836.


DOI:10.3390/ijms26167836
PMID:40869156
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC12386211/
Abstract

Hepatocellular carcinoma (HCC) is the most common liver cancer, with poor survival rates in advanced stages due to late diagnosis, tumor heterogeneity, and therapy resistance. The tumor microenvironment (TME) in HCC has a crucial role in tumor progression, characterized by a complex interaction of immune cells, stromal components, and immunosuppressive signaling pathways. Chronic inflammation driven by viral infections, metabolic dysfunction, and alcohol consumption triggers an immunosuppressive TME, promoting immune evasion and tumor growth. Immune cell populations, such as myeloid-derived suppressor cells, regulatory T cells, and tumor-associated macrophages, contribute to immunosuppression, while cytotoxic T lymphocytes and natural killer cells exert anti-tumor effects. Recent advances in immunotherapy, mainly immune checkpoint inhibitors (ICIs) targeting programmed death-ligand 1 and programmed cell death protein 1 and cytotoxic T-lymphocyte-associated protein 4, have revolutionized HCC treatment, though response rates remain limited. Combined therapies using tyrosine kinase inhibitors, anti-angiogenic agents, and ICIs improve patient outcomes. This review discusses the immunological mechanisms contributing to HCC progression, the role of immune cell subsets in tumor evasion, and therapeutic interventions, from conventional treatments to advanced immunotherapies. Ongoing clinical trials, barriers to effective treatment, and future directions to enhance HCC management and patient survival will also be overviewed.

摘要

肝细胞癌(HCC)是最常见的肝癌,由于诊断较晚、肿瘤异质性和治疗耐药性,晚期患者生存率较低。HCC中的肿瘤微环境(TME)在肿瘤进展中起关键作用,其特征是免疫细胞、基质成分和免疫抑制信号通路之间的复杂相互作用。由病毒感染、代谢功能障碍和饮酒驱动的慢性炎症会引发免疫抑制性TME,促进免疫逃逸和肿瘤生长。髓源性抑制细胞、调节性T细胞和肿瘤相关巨噬细胞等免疫细胞群体有助于免疫抑制,而细胞毒性T淋巴细胞和自然杀伤细胞则发挥抗肿瘤作用。免疫疗法的最新进展,主要是针对程序性死亡配体1、程序性细胞死亡蛋白1和细胞毒性T淋巴细胞相关蛋白4的免疫检查点抑制剂(ICI),彻底改变了HCC的治疗方式,尽管缓解率仍然有限。使用酪氨酸激酶抑制剂、抗血管生成药物和ICI的联合疗法可改善患者预后。本综述讨论了导致HCC进展的免疫机制、免疫细胞亚群在肿瘤逃逸中的作用以及治疗干预措施,从传统治疗到先进的免疫疗法。还将概述正在进行的临床试验、有效治疗的障碍以及提高HCC管理和患者生存率的未来方向。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/71c5/12386211/6fedb0168baf/ijms-26-07836-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/71c5/12386211/1214b4360a41/ijms-26-07836-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/71c5/12386211/1db65046051f/ijms-26-07836-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/71c5/12386211/6fedb0168baf/ijms-26-07836-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/71c5/12386211/1214b4360a41/ijms-26-07836-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/71c5/12386211/1db65046051f/ijms-26-07836-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/71c5/12386211/6fedb0168baf/ijms-26-07836-g003.jpg

相似文献

[1]
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[8]
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[9]
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[10]
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本文引用的文献

[1]
Hepatocellular carcinoma: signaling pathways and therapeutic advances.

Signal Transduct Target Ther. 2025-2-7

[2]
Differences in the intrahepatic expression of immune checkpoint molecules on T cells and natural killer cells in chronic HBV patients.

Front Immunol. 2025-1-15

[3]
Tiragolumab in combination with atezolizumab and bevacizumab in patients with unresectable, locally advanced or metastatic hepatocellular carcinoma (MORPHEUS-Liver): a randomised, open-label, phase 1b-2, study.

Lancet Oncol. 2025-2

[4]
Advancements in Immunotherapeutic Treatments for Hepatocellular Carcinoma: Potential of Combination Therapies.

Int J Mol Sci. 2024-6-21

[5]
Hepatocellular Carcinoma: Beyond the Border of Advanced Stage Therapy.

Cancers (Basel). 2024-5-27

[6]
Prognostic and therapeutic potential of imbalance between PD-1+CD8 and ICOS+Treg cells in advanced HBV-HCC.

Cancer Sci. 2024-8

[7]
Hepatocellular Carcinoma and the Multifaceted Relationship with Its Microenvironment: Attacking the Hepatocellular Carcinoma Defensive Fortress.

Cancers (Basel). 2024-5-11

[8]
Heterogeneity of hepatocellular carcinoma: from mechanisms to clinical implications.

Cancer Gene Ther. 2024-8

[9]
The current status and future of PD-L1 in liver cancer.

Front Immunol. 2023

[10]
Dysregulated cholesterol regulatory genes in hepatocellular carcinoma.

Eur J Med Res. 2023-12-9

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