Bray F, Laversanne M, Sung H, Ferlay J, Siegel RL, Soerjomataram I, et al. Global cancer statistics 2022: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2024;74:229–63.
Google ScholarÂ
Rumgay H, Ferlay J, de Martel C, Georges D, Ibrahim AS, Zheng R, et al. Global, regional and national burden of primary liver cancer by subtype. Eur J Cancer. 2022;161:108–18.
Google ScholarÂ
Zheng J, Wang S, Xia L, Sun Z, Chan KM, Bernards R, et al. Hepatocellular carcinoma: signaling pathways and therapeutic advances. Signal Transduct Target Ther. 2025;10:35.
Google ScholarÂ
Desert R, Gianonne F, Saviano A, Hoshida Y, Heikenwälder M, Nahon P, et al. Improving immunotherapy for the treatment of hepatocellular carcinoma: learning from patients and preclinical models. npj Gut and Liver. 2025;2:s44355-025–00018-y.
Google ScholarÂ
Singal AG, Kudo M, Bruix J. Breakthroughs in hepatocellular carcinoma therapies. Clin Gastroenterol Hepatol. 2023;21:2135–49.
Google ScholarÂ
Xu XF, Xing H, Han J, Li ZL, Lau WY, Zhou YH, et al. Risk factors, patterns, and outcomes of late recurrence after liver resection for hepatocellular carcinoma: a multicenter study from China. JAMA Surg. 2019;154:209–17.
Google ScholarÂ
Wang Y, Deng B. Hepatocellular carcinoma: molecular mechanism, targeted therapy, and biomarkers. Cancer Metastasis Rev. 2023;42:629–52.
Google ScholarÂ
Park JW, Chen M, Colombo M, Roberts LR, Schwartz M, Chen PJ, et al. Global patterns of hepatocellular carcinoma management from diagnosis to death: the BRIDGE study. Liver Int. 2015;35:2155–66.
Google ScholarÂ
Nagahama H, Okada S, Okusaka T, Ishii H, Ikeda M, Nakasuka H, et al. Predictive factors for tumor response to systemic chemotherapy in patients with hepatocellular carcinoma. Jpn J Clin Oncol. 1997;27:321–4.
Google ScholarÂ
Yang C, Zhang H, Zhang L, Zhu AX, Bernards R, Qin W, et al. Evolving therapeutic landscape of advanced hepatocellular carcinoma. Nat Rev Gastroenterol Hepatol. 2023;20:203–22.
Google ScholarÂ
Singal AG, Yarchoan M, Yopp A, Sapisochin G, Pinato DJ, Pillai A. Neoadjuvant and adjuvant systemic therapy in HCC: current status and the future. Hepatol Commun. 2024;8:e0430.
Google ScholarÂ
Qin S, Chen M, Cheng AL, Kaseb AO, Kudo M, Lee HC, et al. Atezolizumab plus bevacizumab versus active surveillance in patients with resected or ablated high-risk hepatocellular carcinoma (IMbrave050): a randomised, open-label, multicentre, phase 3 trial. Lancet. 2023;402:1835–47.
Google ScholarÂ
Abou-Alfa GK, Schwartz L, Ricci S, Amadori D, Santoro A, Figer A, et al. Phase II study of sorafenib in patients with advanced hepatocellular carcinoma. J Clin Oncol. 2006;24:4293–4300.
Google ScholarÂ
Cheng A-L, Kang Y-K, Chen Z, Tsao C-J, Qin S, Kim JS, et al. Efficacy and safety of sorafenib in patients in the Asia-Pacific region with advanced hepatocellular carcinoma: a phase III randomised, double-blind, placebo-controlled trial. Lancet Oncol. 2009;10:25–34.
Google ScholarÂ
Kudo M, Finn RS, Qin S, Han KH, Ikeda K, Piscaglia F, et al. Lenvatinib versus sorafenib in first-line treatment of patients with unresectable hepatocellular carcinoma: a randomised phase 3 non-inferiority trial. Lancet. 2018;391:1163–73.
Google ScholarÂ
Finn RS, Qin S, Ikeda M, Galle PR, Ducreux M, Kim T-Y, et al. Atezolizumab plus Bevacizumab in unresectable hepatocellular carcinoma. N Engl J Med. 2020;382:1894–905.
Google ScholarÂ
Ren Z, Xu J, Bai Y, Xu A, Cang S, Du C, et al. Sintilimab plus a bevacizumab biosimilar (IBI305) versus sorafenib in unresectable hepatocellular carcinoma (ORIENT-32): a randomised, open-label, phase 2–3 study. Lancet Oncol. 2021;22:977–90.
Google ScholarÂ
Abou-Alfa GK, Lau G, Kudo M, Chan SL, Kelley RK, Furuse J, et al. Tremelimumab plus durvalumab in unresectable hepatocellular carcinoma. NEJM Evidence. 2022;1:EVIDoa2100070.
Google ScholarÂ
Kudo M. Adjuvant atezolizumab-bevacizumab after curative therapy for hepatocellular carcinoma. Hepatobiliary Surgery and Nutrition. 2023;12:435–9.
Google ScholarÂ
Xia Y, Tang W, Qian X, Li X, Cheng F, Wang K, et al. Efficacy and safety of camrelizumab plus apatinib during the perioperative period in resectable hepatocellular carcinoma: a single-arm, open-label, phase II clinical trial. J ImmunoTher Cancer. 2022;10:e004656.
Google ScholarÂ
Marron TU, Fiel MI, Hamon P, Fiaschi N, Kim E, Ward SC, et al. Neoadjuvant cemiplimab for resectable hepatocellular carcinoma: a single-arm, open-label, phase 2 trial. Lancet Gastroenterol Hepatol. 2022;7:219–29.
Google ScholarÂ
Kaseb AO, Hasanov E, Cao HST, Xiao L, Vauthey J-N, Lee SS, et al. Perioperative nivolumab monotherapy versus nivolumab plus ipilimumab in resectable hepatocellular carcinoma: a randomised, open-label, phase 2 trial. Lancet Gastroenterol Hepatol. 2022;7:208–18.
Google ScholarÂ
Chick RC, Ruff SM, Pawlik TM. Neoadjuvant systemic therapy for hepatocellular carcinoma. Front Immunol. 2024;15:1355812.
Google ScholarÂ
Guo C, Zhang J, Huang X, Chen Y, Sheng J, Huang X, et al. Preoperative sintilimab plus transarterial chemoembolization for hepatocellular carcinoma exceeding the Milan criteria: a phase II trial. Hepatol Commun. 2023;7:e0054–e0054.
Google ScholarÂ
Yang X, Yang C, Zhang S, Geng H, Zhu AX, Bernards R, et al. Precision treatment in advanced hepatocellular carcinoma. Cancer Cell. 2024;42:180–97.
Google ScholarÂ
Ladd AD, Duarte S, Sahin I, Zarrinpar A. Mechanisms of drug resistance in HCC. Hepatology. 2024;79:926–40.
Google ScholarÂ
Kluger HM, Tawbi HA, Ascierto ML, Bowden M, Callahan MK, Cha E, et al. Defining tumor resistance to PD-1 pathway blockade: recommendations from the first meeting of the SITC immunotherapy resistance taskforce. J Immunother Cancer. 2020;8:e000398.
Google ScholarÂ
Chen S, Cao Q, Wen W, Wang H. Targeted therapy for hepatocellular carcinoma: challenges and opportunities. Cancer Lett. 2019;460:1–9.
Google ScholarÂ
Chen C, Wang Z, Ding Y, Qin Y. Tumor microenvironment-mediated immune evasion in hepatocellular carcinoma. Front Immunol. 2023;14:1133308.
Google ScholarÂ
Argentiero A, Delvecchio A, Fasano R, Andriano A, Caradonna IC, Memeo R, et al. The complexity of the tumor microenvironment in hepatocellular carcinoma and emerging therapeutic developments. J Clin Med. 2023;12:7469.
Google ScholarÂ
Sas Z, Cendrowicz E, Weinhauser I, Rygiel TP. Tumor microenvironment of hepatocellular carcinoma: challenges and opportunities for new treatment options. Int J Mol Sci. 2022;23:3778.
Google ScholarÂ
Akkız H. Emerging role of cancer-associated fibroblasts in progression and treatment of hepatocellular carcinoma. Int J Mol Sci. 2023;24:3941.
Google ScholarÂ
Affo S, Yu LX, Schwabe RF. The role of cancer-associated fibroblasts and fibrosis in liver cancer. Annu Rev Pathol. 2017;12:153–86.
Google ScholarÂ
Peng H, Zhu E, Zhang Y. Advances of cancer-associated fibroblasts in liver cancer. Biomark Res. 2022;10:59.
Google ScholarÂ
Zhang J, Gu C, Song Q, Zhu M, Xu Y, Xiao M, et al. Identifying cancer-associated fibroblasts as emerging targets for hepatocellular carcinoma. Cell Biosci. 2020;10:127.
Google ScholarÂ
Chen Y, McAndrews KM, Kalluri R. Clinical and therapeutic relevance of cancer-associated fibroblasts. Nat Rev Clin Oncol. 2021;18:792–804.
Google ScholarÂ
Filliol A, Saito Y, Nair A, Dapito DH, Yu LX, Ravichandra A, et al. Opposing roles of hepatic stellate cell subpopulations in hepatocarcinogenesis. Nature. 2022;610:356–65.
Google ScholarÂ
Chiavarina B, Ronca R, Otaka Y, Sutton RB, Rezzola S, Yokobori T, et al. Fibroblast-derived prolargin is a tumor suppressor in hepatocellular carcinoma. Oncogene. 2022;41:1410–20.
Google ScholarÂ
Yu L, Shen N, Shi Y, Shi X, Fu X, Li S, et al. Characterization of cancer-related fibroblasts (CAF) in hepatocellular carcinoma and construction of CAF-based risk signature based on single-cell RNA-seq and bulk RNA-seq data. Front Immunol. 2022;13:1009789.
Google ScholarÂ
Melchionna R, Trono P, Di Carlo A, Di Modugno F, Nistico P. Transcription factors in fibroblast plasticity and CAF heterogeneity. J Exp Clin Cancer Res. 2023;42:347.
Google ScholarÂ
Kennel KB, Bozlar M, De Valk AF, Greten FR. Cancer-associated fibroblasts in inflammation and antitumor immunity. Clin Cancer Res. 2023;29:1009–16.
Google ScholarÂ
Liu Y, Dong G, Yu J, Liang P. Integration of single-cell and spatial transcriptomics reveals fibroblast subtypes in hepatocellular carcinoma: spatial distribution, differentiation trajectories, and therapeutic potential. J Transl Med. 2025;23:198.
Google ScholarÂ
Elyada E, Bolisetty M, Laise P, Flynn WF, Courtois ET, Burkhart RA, et al. Cross-species single-cell analysis of pancreatic ductal adenocarcinoma reveals antigen-presenting cancer-associated fibroblasts. Cancer Discov. 2019;9:1102–23.
Google ScholarÂ
Xie Z, Huang J, Li Y, Zhu Q, Huang X, Chen J, et al. Single-cell RNA sequencing revealed potential targets for immunotherapy studies in hepatocellular carcinoma. Sci Rep. 2023;13:18799.
Google ScholarÂ
Wang H, Liang Y, Liu Z, Zhang R, Chao J, Wang M, et al. POSTN(+) cancer-associated fibroblasts determine the efficacy of immunotherapy in hepatocellular carcinoma. J Immunother Cancer. 2024;12:e008721.
Google ScholarÂ
Lin ZY, Chuang YH, Chuang WL. Cancer-associated fibroblasts up-regulate CCL2, CCL26, IL6 and LOXL2 genes related to the promotion of cancer progression in hepatocellular carcinoma cells. Biomed Pharmacother. 2012;66:525–9.
Google ScholarÂ
Zou B, Liu X, Gong Y, Cai C, Li P, Xing S, et al. A novel 12-marker panel of cancer-associated fibroblasts involved in progression of hepatocellular carcinoma. Cancer Manag Res. 2018;10:5303–11.
Google ScholarÂ
Jia CC, Wang TT, Liu W, Fu BS, Hua X, Wang GY, et al. Cancer-associated fibroblasts from hepatocellular carcinoma promote malignant cell proliferation by HGF secretion. PLoS ONE. 2013;8:e63243.
Google ScholarÂ
Liu G, Yang ZF, Sun J, Sun BY, Zhou PY, Zhou C, et al. The LINC00152/miR-205-5p/CXCL11 axis in hepatocellular carcinoma cancer-associated fibroblasts affects cancer cell phenotypes and tumor growth. Cell Oncol. 2022;45:1435–49.
Google ScholarÂ
Sheng L, Lin J, Zhang Y, Chen Y, Ye X, Wang X. CAF-EVs carry lncRNA MAPKAPK5-AS1 into hepatocellular carcinoma cells and promote malignant cell proliferation. Commun Biol. 2024;7:1711.
Google ScholarÂ
Kato K, Fukai M, Hatanaka KC, Takasawa A, Aoyama T, Hayasaka T, et al. Versican secreted by cancer-associated fibroblasts is a poor prognostic factor in hepatocellular carcinoma. Ann Surg Oncol. 2022;29:7135–46.
Google ScholarÂ
Liu J, Chen S, Wang W, Ning BF, Chen F, Shen W, et al. Cancer-associated fibroblasts promote hepatocellular carcinoma metastasis through chemokine-activated hedgehog and TGF-β pathways. Cancer Lett. 2016;379:49–59.
Google ScholarÂ
Xu H, Zhao J, Li J, Zhu Z, Cui Z, Liu R, et al. Cancer-associated fibroblast-derived CCL5 promotes hepatocellular carcinoma metastasis through activating HIF1α/ZEB1 axis. Cell Death Dis. 2022;13:478.
Google ScholarÂ
Liu G, Sun J, Yang ZF, Zhou C, Zhou PY, Guan RY, et al. Cancer-associated fibroblast-derived CXCL11 modulates hepatocellular carcinoma cell migration and tumor metastasis through the circUBAP2/miR-4756/IFIT1/3 axis. Cell Death Dis. 2021;12:260.
Google ScholarÂ
Wang H, Liu F, Wu X, Zhu G, Tang Z, Qu W, et al. Cancer-associated fibroblasts contributed to hepatocellular carcinoma recurrence and metastasis via CD36-mediated fatty-acid metabolic reprogramming. Exp Cell Res. 2024;435:113947.
Google ScholarÂ
Chen S, Morine Y, Tokuda K, Yamada S, Saito Y, Nishi M, et al. Cancer‑associated fibroblast‑induced M2‑polarized macrophages promote hepatocellular carcinoma progression via the plasminogen activator inhibitor‑1 pathway. Int J Oncol. 2021;59:59.
Google ScholarÂ
Cheng JT, Deng YN, Yi HM, Wang GY, Fu BS, Chen WJ, et al. Hepatic carcinoma-associated fibroblasts induce IDO-producing regulatory dendritic cells through IL-6-mediated STAT3 activation. Oncogenesis. 2016;5:e198.
Google ScholarÂ
Dituri F, Mancarella S, Serino G, Chaoul N, Lupo LG, Villa E, et al. Direct and indirect effects of TGFβ on treg transendothelial recruitment in HCC tissue microenvironment. Int J Mol Sci. 2021;22:11765.
Google ScholarÂ
Lin C, Chen Y, Zhang F, Zhu P, Yu L, Chen W. Single-cell RNA sequencing reveals the mediatory role of cancer-associated fibroblast PTN in hepatitis B virus cirrhosis-HCC progression. Gut Pathog. 2023;15:26.
Google ScholarÂ
Xu W, Weng J, Zhao Y, Xie P, Xu M, Liu S, et al. FMO2+cancer-associated fibroblasts sensitize anti-PD-1 therapy in patients with hepatocellular carcinoma. J ImmunoTher Cancer. 2025;13:e011648.
Google ScholarÂ
Zhu GQ, Tang Z, Huang R, Qu WF, Fang Y, Yang R, et al. CD36(+) cancer-associated fibroblasts provide immunosuppressive microenvironment for hepatocellular carcinoma via secretion of macrophage migration inhibitory factor. Cell Discov. 2023;9:25.
Google ScholarÂ
Yang X, Lin Y, Shi Y, Li B, Liu W, Yin W, et al. FAP promotes immunosuppression by cancer-associated fibroblasts in the tumor microenvironment via STAT3-CCL2 signaling. Cancer Res. 2016;76:4124–35.
Google ScholarÂ
Gao J, Li Z, Lu Q, Zhong J, Pan L, Feng C, et al. Single-cell RNA sequencing reveals cell subpopulations in the tumor microenvironment contributing to hepatocellular carcinoma. Front Cell Dev Biol. 2023;11:1194199.
Google ScholarÂ
Bertero T, Oldham WM, Grasset EM, Bourget I, Boulter E, Pisano S, et al. Tumor-stroma mechanics coordinate amino acid availability to sustain tumor growth and malignancy. Cell Metab. 2019;29:124–140 e10.
Google ScholarÂ
Sun B, Lei X, Cao M, Li Y, Yang LY. Hepatocellular carcinoma cells remodel the pro-metastatic tumour microenvironment through recruitment and activation of fibroblasts via paracrine Egfl7 signaling. Cell Commun Signal. 2023;21:180.
Google ScholarÂ
Harris NLE, Vennin C, Conway JRW, Vine KL, Pinese M, Cowley MJ, et al. SerpinB2 regulates stromal remodelling and local invasion in pancreatic cancer. Oncogene. 2017;36:4288–98.
Google ScholarÂ
Bharadwaj AG, Holloway RW, Miller VA, Waisman DM. Plasmin and plasminogen system in the tumor microenvironment: implications for cancer diagnosis, prognosis, and therapy. Cancers. 2021;13:1838.
Google ScholarÂ
Lee JA, Yerbury JJ, Farrawell N, Shearer RF, Constantinescu P, Hatters DM, et al. SerpinB2 (PAI-2) modulates proteostasis via binding misfolded proteins and promotion of cytoprotective inclusion formation. PLoS ONE. 2015;10:e0130136.
Google ScholarÂ
Tsai YT, Li CY, Huang YH, Chang TS, Lin CY, Chuang CH, et al. Galectin-1 orchestrates an inflammatory tumor-stroma crosstalk in hepatoma by enhancing TNFR1 protein stability and signaling in carcinoma-associated fibroblasts. Oncogene. 2022;41:3011–23.
Google ScholarÂ
Jing SY, Liu D, Feng N, Dong H, Wang HQ, Yan X, et al. Spatial multiomics reveals a subpopulation of fibroblasts associated with cancer stemness in human hepatocellular carcinoma. Genome Med. 2024;16:98.
Google ScholarÂ
Cheng Y, Chen X, Feng L, Yang Z, Xiao L, Xiang B, et al. Stromal architecture and fibroblast subpopulations with opposing effects on outcomes in hepatocellular carcinoma. Cell Discov. 2025;11:1.
Google ScholarÂ
Liu Z, Chen M, Zhao R, Huang Y, Liu F, Li B, et al. CAF-induced placental growth factor facilitates neoangiogenesis in hepatocellular carcinoma. Acta Biochim Biophys Sin. 2020;52:18–25.
Google ScholarÂ
Huang B, Huang M, Li Q. Cancer-associated fibroblasts promote angiogenesis of hepatocellular carcinoma by VEGF-mediated EZH2/VASH1 pathway. Technol Cancer Res Treat. 2019;18:1533033819879905.
Google ScholarÂ
Zheng X, Wang P, Li L, Yu J, Yu C, Xu L, et al. Cancer-associated fibroblasts promote vascular invasion of hepatocellular carcinoma via downregulating decorin-integrin β1 signaling. Front Cell Dev Biol. 2021;9:678670.
Google ScholarÂ
Seftor RE, Hess AR, Seftor EA, Kirschmann DA, Hardy KM, Margaryan NV, et al. Tumor cell vasculogenic mimicry: from controversy to therapeutic promise. Am J Pathol. 2012;181:1115–25.
Google ScholarÂ
Yang J, Lu Y, Lin YY, Zheng ZY, Fang JH, He S, et al. Vascular mimicry formation is promoted by paracrine TGF-β and SDF1 of cancer-associated fibroblasts and inhibited by miR-101 in hepatocellular carcinoma. Cancer Lett. 2016;383:18–27.
Google ScholarÂ
She Q, Hu S, Pu X, Guo Q, Mou C, Yang C. The effect of hepatocellular carcinoma-associated fibroblasts on hepatoma vasculogenic mimicry. Am J Cancer Res. 2020;10:4198–210.
Google ScholarÂ
Han J, Won M, Kim JH, Jung E, Min K, Jangili P, et al. Cancer stem cell-targeted bio-imaging and chemotherapeutic perspective. Chem Soc Rev. 2020;49:7856–78.
Google ScholarÂ
Atashzar MR, Baharlou R, Karami J, Abdollahi H, Rezaei R, Pourramezan F, et al. Cancer stem cells: a review from origin to therapeutic implications. J Cell Physiol. 2020;235:790–803.
Google ScholarÂ
Lee TK, Guan XY, Ma S. Cancer stem cells in hepatocellular carcinoma—from origin to clinical implications. Nat Rev Gastroenterol Hepatol. 2022;19:26–44.
Google ScholarÂ
Yang L, Shi P, Zhao G, Xu J, Peng W, Zhang J, et al. Targeting cancer stem cell pathways for cancer therapy. Signal Transduct Target Ther. 2020;5:8.
Google ScholarÂ
Prieto-Vila M, Takahashi RU, Usuba W, Kohama I, Ochiya T. Drug resistance driven by cancer stem cells and their niche. Int J Mol Sci. 2017;18:2574.
Google ScholarÂ
Su Z, Lu C, Zhang F, Liu H, Li M, Qiao M, et al. Cancer-associated fibroblasts-secreted exosomal miR-92a-3p promotes tumor growth and stemness in hepatocellular carcinoma through activation of Wnt/β-catenin signaling pathway by suppressing AXIN1. J Cell Physiol. 2024;239:e31344.
Google ScholarÂ
Bai S, Zhao Y, Chen W, Peng W, Wang Y, Xiong S, et al. The stromal-tumor amplifying STC1-Notch1 feedforward signal promotes the stemness of hepatocellular carcinoma. J Transl Med. 2023;21:236.
Google ScholarÂ
Liu C, Liu L, Chen X, Cheng J, Zhang H, Zhang C, et al. LSD1 stimulates cancer-associated fibroblasts to drive notch3-dependent self-renewal of liver cancer stem-like cells. Cancer Res. 2018;78:938–49.
Google ScholarÂ
Xiong S, Wang R, Chen Q, Luo J, Wang J, Zhao Z, et al. Cancer-associated fibroblasts promote stem cell-like properties of hepatocellular carcinoma cells through IL-6/STAT3/Notch signaling. Am J Cancer Res. 2018;8:302–16.
Google ScholarÂ
Li Y, Wang R, Xiong S, Wang X, Zhao Z, Bai S, et al. Cancer-associated fibroblasts promote the stemness of CD24(+) liver cells via paracrine signaling. J Mol Med. 2019;97:243–55.
Google ScholarÂ
Liu B, Fang X, Kwong DL, Zhang Y, Verhoeft K, Gong L, et al. Targeting TROY-mediated P85a/AKT/TBX3 signaling attenuates tumor stemness and elevates treatment response in hepatocellular carcinoma. J Exp Clin Cancer Res. 2022;41:182.
Google ScholarÂ
Song M, He J, Pan QZ, Yang J, Zhao J, Zhang YJ, et al. Cancer-associated fibroblast-mediated cellular crosstalk supports hepatocellular carcinoma progression. Hepatology. 2021;73:1717–35.
Google ScholarÂ
Luo Q, Wang CQ, Yang LY, Gao XM, Sun HT, Zhang Y, et al. FOXQ1/NDRG1 axis exacerbates hepatocellular carcinoma initiation via enhancing crosstalk between fibroblasts and tumor cells. Cancer Lett. 2018;417:21–34.
Google ScholarÂ
Rogers MP, Kothari A, Read M, Kuo PC, Mi Z. Maintaining myofibroblastic-like cancer-associated fibroblasts by cancer stemness signal transduction feedback loop. Cureus. 2022;14:e29354.
Google ScholarÂ
Zhao Z, Bai S, Wang R, Xiong S, Li Y, Wang X, et al. Cancer-associated fibroblasts endow stem-like qualities to liver cancer cells by modulating autophagy. Cancer Manag Res. 2019;11:5737–44.
Google ScholarÂ
Zhao J, Li R, Li J, Chen Z, Lin Z, Zhang B, et al. CAFs-derived SCUBE1 promotes malignancy and stemness through the Shh/Gli1 pathway in hepatocellular carcinoma. J Transl Med. 2022;20:520.
Google ScholarÂ
Xiao H, Yao Z, Li T, Fang X, Xu X, Hu S, et al. SERPINH1 secretion by cancer-associated fibroblasts promotes hepatocellular carcinoma malignancy through SENP3-mediated SP1/SQLE pathway. Int Immunopharmacol. 2025;150:114259.
Google ScholarÂ
Hamaya S, Oura K, Morishita A, Masaki T. Cisplatin in liver cancer therapy. Int J Mol Sci. 2023;24:10858.
Google ScholarÂ
Chang Y, Jeong SW, Young Jang J, Jae Kim Y. Recent updates of transarterial chemoembolilzation in hepatocellular carcinoma. Int J Mol Sci. 2020;21:8165.
Google ScholarÂ
Manjunatha N, Ganduri V, Rajasekaran K, Duraiyarasan S, Adefuye M. Transarterial chemoembolization and unresectable hepatocellular carcinoma: a narrative review. Cureus. 2022;14:e28439.
Google ScholarÂ
Iwamoto H, Shimose S, Shirono T, Niizeki T, Kawaguchi T. Hepatic arterial infusion chemotherapy for advanced hepatocellular carcinoma in the era of chemo-diversity. Clin Mol Hepatol. 2023;29:593–604.
Google ScholarÂ
Zheng K, Zhu X, Fu S, Cao G, Li WQ, Xu L, et al. Sorafenib plus hepatic arterial infusion chemotherapy versus sorafenib for hepatocellular carcinoma with major portal vein tumor thrombosis: a randomized trial. Radiology. 2022;303:455–64.
Google ScholarÂ
He M, Li Q, Zou R, Shen J, Fang W, Tan G, et al. Sorafenib plus hepatic arterial infusion of oxaliplatin, fluorouracil, and leucovorin vs sorafenib alone for hepatocellular carcinoma with portal vein invasion: a randomized clinical trial. JAMA Oncol. 2019;5:953–60.
Google ScholarÂ
Luo Y, Tan H, Yu T, Tian J, Shi H. A novel artificial neural network prognostic model based on a cancer-associated fibroblast activation score system in hepatocellular carcinoma. Front Immunol. 2022;13:927041.
Google ScholarÂ
Chen Q, Wang X, Zheng Y, Ye T, Liu J, Wang JQ, et al. Cancer-associated fibroblasts contribute to the immunosuppressive landscape and influence the efficacy of the combination therapy of PD-1 inhibitors and antiangiogenic agents in hepatocellular carcinoma. Cancer. 2023;129:3405–16.
Google ScholarÂ
Dong W, Xie Y, Huang H. Prognostic value of cancer-associated fibroblast-related gene signatures in hepatocellular carcinoma. Front Endocrinol. 2022;13:884777.
Google ScholarÂ
Liu J, Li P, Wang L, Li M, Ge Z, Noordam L, et al. Cancer-associated fibroblasts provide a stromal niche for liver cancer organoids that confers trophic effects and therapy resistance. Cell Mol Gastroenterol Hepatol. 2021;11:407–31.
Google ScholarÂ
Zhou Y, Tang W, Zhuo H, Zhu D, Rong D, Sun J, et al. Cancer-associated fibroblast exosomes promote chemoresistance to cisplatin in hepatocellular carcinoma through circZFR targeting signal transducers and activators of transcription (STAT3)/ nuclear factor -kappa B (NF-κB) pathway. Bioengineered. 2022;13:4786–97.
Google ScholarÂ
Peng H, Xue R, Ju Z, Qiu J, Wang J, Yan W, et al. Cancer-associated fibroblasts enhance the chemoresistance of CD73(+) hepatocellular carcinoma cancer cells via HGF-Met-ERK1/2 pathway. Ann Transl Med. 2020;8:856.
Google ScholarÂ
Vogel A, Meyer T, Sapisochin G, Salem R, Saborowski A. Hepatocellular carcinoma. Lancet. 2022;400:1345–62.
Google ScholarÂ
Fu J, Wang H. Precision diagnosis and treatment of liver cancer in China. Cancer Lett. 2018;412:283–8.
Google ScholarÂ
Li L, Wang H. Heterogeneity of liver cancer and personalized therapy. Cancer Lett. 2016;379:191–7.
Google ScholarÂ
Khawar IA, Park JK, Jung ES, Lee MA, Chang S, Kuh HJ. Three-dimensional mixed-cell spheroids mimic stroma-mediated chemoresistance and invasive migration in hepatocellular carcinoma. Neoplasia. 2018;20:800–12.
Google ScholarÂ
Poddar MS, Chu YD, Pendharkar G, Liu CH, Yeh CT. Exploring cancer-associated fibroblast-induced resistance to tyrosine kinase inhibitors in hepatoma cells using a liver-on-a-chip model. Lab Chip. 2024;24:5043–54.
Google ScholarÂ
Shirbhate E, Singh V, Kore R, Vishwakarma S, Veerasamy R, Tiwari AK, et al. The role of cytokines in activation of tumour-promoting pathways and emergence of cancer drug resistance. Curr Top Med Chem. 2024;24:523–40.
Google ScholarÂ
Jones VS, Huang RY, Chen LP, Chen ZS, Fu L, Huang RP. Cytokines in cancer drug resistance: cues to new therapeutic strategies. Biochim Biophys Acta. 2016;1865:255–65.
Google ScholarÂ
Kumari N, Dwarakanath BS, Das A, Bhatt AN. Role of interleukin-6 in cancer progression and therapeutic resistance. Tumour Biol. 2016;37:11553–72.
Google ScholarÂ
Lv KJ, Yu SZ, Wang Y, Zhang SR, Li WY, Hou J, et al. Cancer-associated fibroblasts promote the progression and chemoresistance of HCC by inducing IGF-1. Cell Signal. 2024;124:111378.
Google ScholarÂ
Gao L, Morine Y, Yamada S, Saito Y, Ikemoto T, Tokuda K, et al. The BAFF/NFκB axis is crucial to interactions between sorafenib-resistant HCC cells and cancer-associated fibroblasts. Cancer Sci. 2021;112:3545–54.
Google ScholarÂ
Ghanem I, Riveiro ME, Paradis V, Faivre S, de Parga PM, Raymond E. Insights on the CXCL12-CXCR4 axis in hepatocellular carcinoma carcinogenesis. Am J Transl Res. 2014;6:340–52.
Google ScholarÂ
Teicher BA, Fricker SP. CXCL12 (SDF-1)/CXCR4 pathway in cancer. Clin Cancer Res. 2010;16:2927–31.
Google ScholarÂ
Zhao J, Lin E, Bai Z, Jia Y, Wang B, Dai Y, et al. Cancer-associated fibroblasts induce sorafenib resistance of hepatocellular carcinoma cells through CXCL12/FOLR1. BMC Cancer. 2023;23:1198.
Google ScholarÂ
Gao B, Wang Y, Sun Z, Tang H, Cao Y, Jiang H et al. NQO1/p65/CXCL12 axis-recruited tregs mediate resistance to anti-PD-1 plus lenvatinib therapy in PIVKA-II-positive hepatocellular carcinoma. Adv Sci 2025;12:e11152.
Yuan Q, Zhang J, Liu Y, Chen H, Liu H, Wang J, et al. MyD88 in myofibroblasts regulates aerobic glycolysis-driven hepatocarcinogenesis via ERK-dependent PKM2 nuclear relocalization and activation. J Pathol. 2022;256:414–26.
Google ScholarÂ
Feng J, Li J, Wu L, Yu Q, Ji J, Wu J, et al. Emerging roles and the regulation of aerobic glycolysis in hepatocellular carcinoma. J Exp Clin Cancer Res. 2020;39:126.
Google ScholarÂ
Zhang P, Chen S, Cai J, Song L, Quan B, Wan J, et al. GALNT6 drives lenvatinib resistance in hepatocellular carcinoma through autophagy and cancer-associated fibroblast activation. Cell Oncol. 2024;47:2439–60.
Google ScholarÂ
Eun JW, Yoon JH, Ahn HR, Kim S, Kim YB, Lim SB, et al. Cancer-associated fibroblast-derived secreted phosphoprotein 1 contributes to resistance of hepatocellular carcinoma to sorafenib and lenvatinib. Cancer Commun. 2023;43:455–79.
Google ScholarÂ
Peng H, Yang M, Feng K, Lv Q, Zhang Y. Semaphorin 3C (Sema3C) reshapes stromal microenvironment to promote hepatocellular carcinoma progression. Signal Transduct Target Ther. 2024;9:169.
Google ScholarÂ
Chen W, Wu J, Shi H, Wang Z, Zhang G, Cao Y, et al. Hepatic stellate cell coculture enables sorafenib resistance in Huh7 cells through HGF/c-Met/Akt and Jak2/Stat3 pathways. Biomed Res Int. 2014;2014:764981.
Google ScholarÂ
Qin W, Wang L, Tian H, Wu X, Xiao C, Pan Y, et al. CAF-derived exosomes transmitted Gremlin-1 promotes cancer progression and decreases the sensitivity of hepatoma cells to sorafenib. Mol Carcinog. 2022;61:764–75.
Google ScholarÂ
Zhang Y, Pan Q, Shao Z. Extracellular vesicles derived from cancer-associated fibroblasts carry tumor-promotive microRNA-1228-3p to enhance the resistance of hepatocellular carcinoma cells to sorafenib. Hum Cell. 2023;36:296–311.
Google ScholarÂ
Zaki MYW, Alhasan SF, Shukla R, McCain M, Laszczewska M, Geh D, et al. Sulfatase-2 from Cancer-associated fibroblasts: an environmental target for hepatocellular carcinoma? Liver Cancer. 2022;11:540–57.
Google ScholarÂ
Dong Y, Chen Y, Wang Y, Zhao X, Zi R, Hao J, et al. Cancer-associated fibroblasts-derived fibronectin extra domain A promotes sorafenib resistance in hepatocellular carcinoma cells by activating SHMT1. Genes Dis. 2024;11:101330.
Google ScholarÂ
Yang H, Chen D, Wu Y, Zhou H, Diao W, Liu G, et al. A feedback loop of PPP and PI3K/AKT signal pathway drives regorafenib-resistance in HCC. Cancer Metab. 2023;11:27.
Google ScholarÂ
Qin Y, Han S, Yu Y, Qi D, Ran M, Yang M, et al. Lenvatinib in hepatocellular carcinoma: resistance mechanisms and strategies for improved efficacy. Liver Int. 2024;44:1808–31.
Google ScholarÂ
Yang T, Zhang S, Nie K, Cheng C, Peng X, Huo J, et al. ZNF207-driven PRDX1 lactylation and NRF2 activation in regorafenib resistance and ferroptosis evasion. Drug Resist Updates. 2025;82:101274.
Google ScholarÂ
Wang Z, Wang Y, Gao P, Ding J. Immune checkpoint inhibitor resistance in hepatocellular carcinoma. Cancer Letters. 2023;555:216038.
Google ScholarÂ
Llovet JM, Castet F, Heikenwalder M, Maini MK, Mazzaferro V, Pinato DJ, et al. Immunotherapies for hepatocellular carcinoma. Nat Rev Clin Oncol. 2022;19:151–72.
Google ScholarÂ
Liu Y, Xun Z, Ma K, Liang S, Li X, Zhou S, et al. Identification of a tumour immune barrier in the HCC microenvironment that determines the efficacy of immunotherapy. J Hepatol. 2023;78:770–82.
Google ScholarÂ
Li Z, Pai R, Gupta S, Currenti J, Guo W, Di Bartolomeo A, et al. Presence of onco-fetal neighborhoods in hepatocellular carcinoma is associated with relapse and response to immunotherapy. Nat Cancer. 2024;5:167–86.
Google ScholarÂ
Zhu Z, Zhang K, Wu W, Zhou J, Zhang M, Chen J, et al. POSTN(+) CAF-derived migrasomes drive hepatocellular carcinoma progression and confer resistance to immunotherapy. Research. 2025;8:0950.
Google ScholarÂ
Li Y, Huan C, Sun H, Zhang W, Guo Z, Li C et al. Spatial transcriptomics and snRNA-seq expose CAF niches orchestrating dual stromal-immune barriers in hepatocellular carcinoma. Adv Sci 2025;12:e14661.
Yu L, Liu Q, Huo J, Wei F, Guo W. Cancer-associated fibroblasts induce immunotherapy resistance in hepatocellular carcinoma animal model. Cell Mol Biol. 2020;66:36–40.
Google ScholarÂ
Wang G, Zhou Z, Jin W, Zhang X, Zhang H, Wang X. Single-cell transcriptome sequencing reveals spatial distribution of IL34(+) cancer-associated fibroblasts in hepatocellular carcinoma tumor microenvironment. NPJ Precis Oncol. 2023;7:133.
Google ScholarÂ
Park JG, Roh PR, Kang MW, Cho SW, Hwangbo S, Jung HD, et al. Intrahepatic IgA complex induces polarization of cancer-associated fibroblasts to matrix phenotypes in the tumor microenvironment of HCC. Hepatology. 2024;80:1074–86.
Google ScholarÂ
Cheng Y, Li H, Deng Y, Tai Y, Zeng K, Zhang Y, et al. Cancer-associated fibroblasts induce PDL1+ neutrophils through the IL6-STAT3 pathway that foster immune suppression in hepatocellular carcinoma. Cell Death Dis. 2018;9:422.
Google ScholarÂ
Chen P, Geng H, Ma B, Zhang Y, Zhu Z, Li M, et al. Integrating spatial omics and single-cell mass spectrometry imaging reveals tumor-host metabolic interplay in hepatocellular carcinoma. Proc Natl Acad Sci USA. 2025;122:e2505789122.
Google ScholarÂ
Murai H, Kodama T, Maesaka K, Tange S, Motooka D, Suzuki Y, et al. Multiomics identifies the link between intratumor steatosis and the exhausted tumor immune microenvironment in hepatocellular carcinoma. Hepatology. 2023;77:77–91.
Google ScholarÂ
Prawira A, Xu H, Mei Y, Leow WQ, Nasir NJM, Reolo MJ, et al. Targeting Treg-fibroblast interaction to enhance immunotherapy in steatotic liver disease-related hepatocellular carcinoma. Gut. 2025;75:105–18.
Google ScholarÂ
Shang H, Lu L, Fan M, Lu Y, Shi X, Lu H. Exosomal circHIF1A derived from hypoxic-induced carcinoma-associated fibroblasts promotes hepatocellular carcinoma cell malignant phenotypes and immune escape. Int Immunopharmacol. 2024;138:112282.
Google ScholarÂ
Feng H, Liu J, Jia H, Bu X, Yang W, Su P. Cancer-associated fibroblasts-derived exosomal ZNF250 promotes the proliferation, migration, invasion, and immune escape of hepatocellular carcinoma cells by transcriptionally activating PD-L1. J Biochem Mol Toxicol. 2024;38:e23778.
Google ScholarÂ
Gan L, Lu T, Lu Y, Song H, Zhang J, Zhang K, et al. Endosialin-positive CAFs promote hepatocellular carcinoma progression by suppressing CD8(+) T cell infiltration. J Immunother Cancer. 2024;12:e009111.
Google ScholarÂ
Ye J, Tian W, Zheng B, Zeng T. Identification of cancer-associated fibroblasts signature for predicting the prognosis and immunotherapy response in hepatocellular carcinoma. Medicine. 2023;102:e35938.
Google ScholarÂ
Guo C, Zhang W, Zhang Q, Su Y, Hou X, Chen Q, et al. Novel dual CAFs and tumour cell targeting pH and ROS dual sensitive micelles for targeting delivery of paclitaxel to liver cancer. Artif Cells Nanomed Biotechnol. 2023;51:170–9.
Google ScholarÂ
Gulati R, Fleifil Y, Jennings K, Bondoc A, Tiao G, Geller J, et al. Inhibition of histone deacetylase activity increases cisplatin efficacy to eliminate metastatic cells in pediatric liver cancers. Cancers. 2024;16:2300.
Google ScholarÂ
Yin X, Zhao X, Shen Y, Xie W, He C, Guo J, et al. Nanoparticle-mediated dual targeting of stromal and immune components to overcome fibrotic and immunosuppressive barriers in hepatocellular carcinoma. J Control Release. 2025;383:113783.
Google ScholarÂ
Yamanaka T, Harimoto N, Yokobori T, Muranushi R, Hoshino K, Hagiwara K, et al. Conophylline inhibits hepatocellular carcinoma by inhibiting activated cancer-associated fibroblasts through suppression of G protein-coupled receptor 68. Mol Cancer Ther. 2021;20:1019–28.
Google ScholarÂ
Sun L, Wang Y, Wang L, Yao B, Chen T, Li Q, et al. Resolvin D1 prevents epithelial-mesenchymal transition and reduces the stemness features of hepatocellular carcinoma by inhibiting paracrine of cancer-associated fibroblast-derived COMP. J Exp Clin Cancer Res. 2019;38:170.
Google ScholarÂ
Huynh H, Ng WH. Reactivation of the PI3K/mTOR signaling pathway confers resistance to the FGFR4 inhibitor FGF401. Int J Mol Sci. 2025;26:9818.
Google ScholarÂ
Mercade TM, Moreno V, John B, Morris JC, Sawyer MB, Yong WP, et al. A phase I study of H3B-6527 in hepatocellular carcinoma (HCC) or intrahepatic cholangiocarcinoma (ICC) patients (pts). J Clin Oncol. 2019;37:4095–4095.
Google ScholarÂ
Zhou M, Zhu S, Xu C, Liu B, Shen J. A phase Ib/II study of BLU-554, a fibroblast growth factor receptor 4 inhibitor in combination with CS1001, an anti-PD-L1, in patients with locally advanced or metastatic hepatocellular carcinoma. Investig New Drugs. 2023;41:162–7.
Google ScholarÂ
Kelley RK, Gane E, Assenat E, Siebler J, Galle PR, Merle P, et al. A phase 2 study of galunisertib (TGF-beta1 receptor type I inhibitor) and sorafenib in patients with advanced hepatocellular carcinoma. Clin Transl Gastroenterol. 2019;10:e00056.
Google ScholarÂ
Yang J, Xu Z, Lan H, Zong W, Xia Y, Feng H, et al. Biomimetic dual-engine nanodisruptor degrades extracellular matrix and hijacks TAM2 to unlock deep immune infiltration in HCC. Small. 2025;21:e08241.
Google ScholarÂ
Yao Y, Yang K, Wang Q, Zhu Z, Li S, Li B, et al. Prediction of CAF-related genes in immunotherapy and drug sensitivity in hepatocellular carcinoma: a multi-database analysis. Genes Immun. 2024;25:55–65.
Google ScholarÂ
Sin SQ, Mohan CD, Goh RMW-J, You M, Nayak SC, Chen L, et al. Hypoxia signaling in hepatocellular carcinoma: Challenges and therapeutic opportunities. Cancer and Metastasis Rev. 2022;42:741–64.
Google ScholarÂ
