Cancer-associated fibroblasts in hepatocellular carcinoma: origins, heterogeneity, and therapeutic implications

Hepatocellular carcinoma (HCC) is a globally prevalent malignancy. This disease often progresses rapidly, resulting in many patients being diagnosed at a late stage, making early detection and intervention a major clinical challenge. Postoperative recurrence and metastasis rates remain significantly...

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Main Authors: Xin Shi, Weixiong Zhu, Jianpeng Zhang, Chuanlei Fan, Jing Zhang
Format: Article
Language:English
Published: Frontiers Media S.A. 2025-07-01
Series:Frontiers in Immunology
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Online Access:https://www.frontiersin.org/articles/10.3389/fimmu.2025.1620075/full
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author Xin Shi
Weixiong Zhu
Jianpeng Zhang
Chuanlei Fan
Jing Zhang
author_facet Xin Shi
Weixiong Zhu
Jianpeng Zhang
Chuanlei Fan
Jing Zhang
author_sort Xin Shi
collection DOAJ
description Hepatocellular carcinoma (HCC) is a globally prevalent malignancy. This disease often progresses rapidly, resulting in many patients being diagnosed at a late stage, making early detection and intervention a major clinical challenge. Postoperative recurrence and metastasis rates remain significantly high, and no effective prevention strategies are currently available. Cancer-associated fibroblasts (CAFs) are essential components in the reorganization of the tumor microenvironment (TME), as they can modulate cancer cell proliferation, migration, invasion, and chemoresistance through diverse mechanisms or signaling pathways, including the release of cytokines, remodeling of the extracellular matrix, and the evasion of the immune response. This review offers a detailed overview of the cellular origins, subtype diversity, and functional differences among CAFs. In addition, it depicts the expression profiles of key markers in various CAF subtypes and clarifies essential signaling pathways and mechanisms of CAFs. Additionally, we discuss current and future therapeutic strategies targeting CAFs in the context of HCC. This review provides critical insights into future studies on novel therapeutic approaches for CAFs.
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spelling doaj-art-993c8853db7f4c37a41d78b7db89ccdb2025-08-20T02:39:41ZengFrontiers Media S.A.Frontiers in Immunology1664-32242025-07-011610.3389/fimmu.2025.16200751620075Cancer-associated fibroblasts in hepatocellular carcinoma: origins, heterogeneity, and therapeutic implicationsXin Shi0Weixiong Zhu1Jianpeng Zhang2Chuanlei Fan3Jing Zhang4Department of Oncology, Taizhou Second People’s Hospital Affiliated to Yangzhou University, Taizhou, Jiangsu, ChinaThe Second Hospital of Lanzhou University, Lanzhou, Gansu, ChinaDepartment of Urology, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong, ChinaDepartment of Gastrointestinal Surgery, Jiangxi Province Hospital of Integrated Chinese and Western Medicine, Nanchang, Jiangxi, ChinaDepartment of Oncology, Taizhou Second People’s Hospital Affiliated to Yangzhou University, Taizhou, Jiangsu, ChinaHepatocellular carcinoma (HCC) is a globally prevalent malignancy. This disease often progresses rapidly, resulting in many patients being diagnosed at a late stage, making early detection and intervention a major clinical challenge. Postoperative recurrence and metastasis rates remain significantly high, and no effective prevention strategies are currently available. Cancer-associated fibroblasts (CAFs) are essential components in the reorganization of the tumor microenvironment (TME), as they can modulate cancer cell proliferation, migration, invasion, and chemoresistance through diverse mechanisms or signaling pathways, including the release of cytokines, remodeling of the extracellular matrix, and the evasion of the immune response. This review offers a detailed overview of the cellular origins, subtype diversity, and functional differences among CAFs. In addition, it depicts the expression profiles of key markers in various CAF subtypes and clarifies essential signaling pathways and mechanisms of CAFs. Additionally, we discuss current and future therapeutic strategies targeting CAFs in the context of HCC. This review provides critical insights into future studies on novel therapeutic approaches for CAFs.https://www.frontiersin.org/articles/10.3389/fimmu.2025.1620075/fullhepatocellular carcinoma (HCC)cancer-associated fibroblasts (CAFs)tumor microenvironment (TME)therapeutic resistanceimmune evasion
spellingShingle Xin Shi
Weixiong Zhu
Jianpeng Zhang
Chuanlei Fan
Jing Zhang
Cancer-associated fibroblasts in hepatocellular carcinoma: origins, heterogeneity, and therapeutic implications
Frontiers in Immunology
hepatocellular carcinoma (HCC)
cancer-associated fibroblasts (CAFs)
tumor microenvironment (TME)
therapeutic resistance
immune evasion
title Cancer-associated fibroblasts in hepatocellular carcinoma: origins, heterogeneity, and therapeutic implications
title_full Cancer-associated fibroblasts in hepatocellular carcinoma: origins, heterogeneity, and therapeutic implications
title_fullStr Cancer-associated fibroblasts in hepatocellular carcinoma: origins, heterogeneity, and therapeutic implications
title_full_unstemmed Cancer-associated fibroblasts in hepatocellular carcinoma: origins, heterogeneity, and therapeutic implications
title_short Cancer-associated fibroblasts in hepatocellular carcinoma: origins, heterogeneity, and therapeutic implications
title_sort cancer associated fibroblasts in hepatocellular carcinoma origins heterogeneity and therapeutic implications
topic hepatocellular carcinoma (HCC)
cancer-associated fibroblasts (CAFs)
tumor microenvironment (TME)
therapeutic resistance
immune evasion
url https://www.frontiersin.org/articles/10.3389/fimmu.2025.1620075/full
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