Volume 282, June 2026, 156425Author links open overlay panelXiu Yan, Xiaoying Dong, Liang Yao, Meihua Guo, Ning WangShow moreAbstract

Hepatocellular carcinoma (HCC) is known as one of the poor-prognosis malignancies. HCC stroma contains a complex ecosystem. Malignant cells in HCC orchestrate intricate cellular interactions and signaling networks to maintain expansion. The tumor microenvironment (TME) in HCC contains various cells with remarkable plasticity, enabling cancer cells to withstand various therapeutic interventions through multiple resistance mechanisms. Upon exposure to chemotherapy or radiation, HCC cells activate sophisticated DNA damage response (DDR) pathways, cell-cycle checkpoints, and immune-evasion mechanisms. Beyond these mechanisms, HCC employs diverse pro-survival strategies, particularly through the upregulation of anti-apoptotic, angiogenesis, and tyrosine kinases, as well as autophagy modulation. The immunosuppressive landscape of HCC further compounds therapeutic resistance, where cancer-associated fibroblasts (CAFs) serve as key architects in restructuring the stromal compartment. Myeloid-derived suppressor cells (MDSCs), regulatory T cells (Tregs), neutrophils, and macrophages collectively establish an immunologically "cold" environment that shields tumor cells from both therapeutic agents and immune surveillance. These cellular interactions occur through an elaborate network of cytokines, chemokines, and metabolic intermediates. This review aims to dissect these multifaceted interactions within the HCC microenvironment and explore emerging strategies to disrupt these communication networks, potentially offering novel approaches to enhance the efficacy of conventional chemotherapy and radiation treatment through targeted sensitization.

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Access through your organizationSection snippetsBackground

HCC is the most well-known and prevalent primary liver malignancy [1]. This malignancy is ranked as the fourth leading cause of cancer-related mortality worldwide [2]. The incidence of this cancer has been steadily rising over the past decades [3]. The etiology of HCC is intricately correlated with chronic liver diseases, predominantly viral hepatitis B and C infections, alcohol-induced liver disease, and non-alcoholic steatohepatitis [4]. The geographic distribution of HCC exhibits notable

TME in HCC: Cell, interactions, and secretions

The TME is central to therapeutic resistance in HCC through several interactions. Stromal and immune cells, the ECM, soluble factors, and physical conditions create a dynamic environment that protects tumor cells from the immune system and anticancer agents. Immune-suppressive cell populations blunt CTLs and NK cell activity through checkpoints, metabolic competition, and inhibitory cytokines. Stromal cells remodel ECM and enhance IFP, thereby limiting drug penetration [22]. Abnormal

Treatment modalities: Pivotal role of chemo/radiotherapy

HCC can be managed using different modalities tailored to tumor stage, liver function, performance status, and comorbidities. Curative-intent options include surgical resection and liver transplantation for patients who meet some strict criteria [105]. Locoregional therapies, including radiofrequency or microwave ablation, TACE, TARE, and HAIC, are another part of treatment options to control HCC in intermediate or locally advanced stages. In addition, these modalities can be suggested to

TME in chemotherapy/radiotherapy of HCC: Interactions and potential modulations

As reviewed, the TME in HCC includes various cells and several released molecules that can be activated in response to chemotherapy, radiotherapy, ICIs, and TKIs. A deep knowledge of these interactions and responses can give us an opportunity to select potential targets for modulating resistance in HCC to various antitumor modalities. In the following subsections, we separately discuss microenvironmental determinants of resistance to systemic chemotherapy, HAIC/TACE‑associated intra‑arterial

CTLs and NK cells in HCC chemo/radiotherapy

CTLs and NK cells develop the central antitumor immunity in HCC. However, as explained earlier, these cells can be exhausted by direct interactions and released factors by cancer cells, CAFs, MDSCs, Tregs, and M2 TAMs. T lymphocytes are among the most sensitive cells to clastogenic effects of radiation and other ROS-generating agents like some chemotherapy drugs. Therefore, radiotherapy and chemotherapy can reduce the number of CTLs by directly inducing apoptosis in these cells. However,

CAFs in HCC chemo/radiotherapy

CAFs are among the most critical components in the tumor that induce resistance to various anticancer agents, including chemotherapy and radiotherapy. As explained, this resistance is mediated by releasing and expressing various molecules. IGF-1 is one of these agents. Exposure of HCC cells to CAF-conditioned medium can increase proliferation, migration, and invasion, and reduce apoptosis after chemotherapy. These functional changes are correlated with rapid phosphorylation of IGF1R and

HSCs in HCC chemo/radiotherapy

HSCs can stimulate HCC growth and resistance to cell death by releasing growth factors, cytokines, and ECM development, as explained earlier. These factors and interactions can induce chemo/radioresistance in HCC. HGF is a key factor released by HSCs that induces chemoresistance. HGF can induce EMT and stemness in HCC cells by inducing Met phosphorylation, upregulation of N-cadherin and vimentin, and nuclear translocation of β-catenin and in these cancer cells. These changes have been shown to

TAMs and Kupffer cells in HCC chemo/radiotherapy

As explained, macrophages can cause different effects on HCC depending on their polarization. However, the immunosuppressive microenvironment of HCC can mainly render polarization of macrophages toward the M2 phenotype. Therefore, macrophages are among the most immunosuppressive cells in HCC and contribute to chemo/radiotherapy resistance. It has been uncovered that M2 TAMs can release CXCL6, which can engage with CXCR4 on hepatic cancer cells. Activation of CXCR4 can stimulate NF-κB and p38

MDSCs in HCC chemo/radiotherapy

High frequency of MDSCs can predict poor prognosis and lower survival for patients who undergo radiotherapy or HAIC [203], [204]. On the other hand, chemotherapy and radiation can stimulate the recruitment of MDSCs. This effect can contribute to chemo/radioresistance of HCC. It has been revealed that 5-FU-resistant HCC cells can stimulate the recruitment of MDSCs by releasing IL-6. The recruited MDSCs then suppress antitumor immunity and induce resistance to chemotherapy by releasing and

Tregs in HCC chemo/radiotherapy

Tregs have various subsets, and their effects on some cancers might be complex. However, it seems that a higher number of intratumoral Tregs in HCC can cause poorer prognosis [212]. Some limited experiments have investigated the effects of radiation and chemotherapy on Tregs in HCC. In contrast to other subsets of T cells, Tregs are radioresistant. Activation of Akt in these cells following exposure to radiation can suppress apoptosis [213]. However, a study reported that a low dose of spleen

Hypoxia and altered metabolism in HCC chemo/radiotherapy

Hypoxia is one of the most important properties of the HCC microenvironment that affects several signaling pathways in cancer cells and other stromal and immune cells. Hypoxia is known as a key inducer of resistance to both chemotherapy and radiotherapy by inducing HIF-1α, angiogenesis, metastasis, alteration of tumor metabolism, and reducing ROS effects on cancer cells. SIRT1 is one of the key mediators of radioresistance in HCC cells that acts through inhibiting the C-Myc/p53 axis.

Current challenges and future directions

Durable response to chemo/radiosensitization in HCC remains as a challenge. Most treatment regimens prioritize malignant cells over microenvironmental targets. This strategy neglects key resistance circuits intact, including CAF-mediated matrix remodeling, TME-induced immunosuppression, and hypoxia/altered metabolism-driven stress tolerance. As explained, CAFs remodel ECM and raise IFP, which compress microvessels, limit drug delivery, and worsen tumor hypoxia. All these effects reduce

Conclusion

The tumor ecosystem in HCC exerts several impacts in cancer cells in response to chemotherapy and radiotherapy. Cells such as CAFs, MDSCs, TAMs, Tregs, NK and CTLs form a dynamic network that shapes antigen handling, immune cell trafficking and effector function after exposure to chemotherapy or radiotherapy. ICD triggered by SBRT, IMRT and some certain chemotherapy drugs like oxaliplatin and cisplatin reliably increases antigen release, DAMP exposure and type I IFN signaling which can prime CD8

CRediT authorship contribution statement

Ning Wang: Writing – review & editing, Writing – original draft. Meihua Guo: Writing – review & editing, Writing – original draft, Supervision. Xiu Yan: Writing – original draft. Liang Yao: Writing – original draft. Xiaoying Dong: Writing – original draft.

Declaration of Competing Interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

References (249)S. Chakraborty et al.Agrin as a Mechanotransduction Signal Regulating YAP through the Hippo Pathway

Cell Rep.

(2017 Mar 7)

C.-Y. Hsu et al.Cancer-associated fibroblast-derived exosomes in cancer progression: A focus on hepatocellular carcinoma

Exp. Cell Res.

(2025)

Y. Xia et al.Chemokine CCL5 immune subtypes of human liver cancer with prognostic significance

Int. Immunopharmacol.

(2022)

V. Kumar et al.The Nature of Myeloid-Derived Suppressor Cells in the Tumor Microenvironment

Trends Immunol.

(2016)

O.W.H. Yeung et al.Alternatively activated (M2) macrophages promote tumour growth and invasiveness in hepatocellular carcinoma

J. Hepatol.

(2015)

L. Du et al.Shp2 Deficiency in Kupffer Cells and Hepatocytes Aggravates Hepatocarcinogenesis by Recruiting Non-Kupffer Macrophages

Cell. Mol. Gastroenterol. Hepatol.

(2023)

A. Jamshidi-Parsian et al.Tumor-endothelial cell interaction in an experimental model of human hepatocellular carcinoma

Exp. Cell Res.

(2018)

K. Liu et al.Vessels that encapsulate tumour clusters vascular pattern in hepatocellular carcinoma

JHEP Rep.

(2023)

X.X. Xiong et al.Advances in Hypoxia-Mediated Mechanisms in Hepatocellular Carcinoma

Mol. Pharmacol.

(2017)

M. Swellam et al.Association of nonalcoholic fatty liver disease with a single nucleotide polymorphism on the gene encoding leptin receptor

IUBMB life

(2012)

R.A. Youness et al.A comprehensive insight and in silico analysis of CircRNAs in hepatocellular carcinoma: a step toward ncRNA-based precision medicine

Cells

(2024)

A.G. Singal et al.Global trends in hepatocellular carcinoma epidemiology: implications for screening, prevention and therapy

Nat. Rev. Clin. Oncol.

(2023)

C. Campbell et al.Risk factors for the development of hepatocellular carcinoma (HCC) in chronic hepatitis B virus (HBV) infection: a systematic review and meta-analysis

J. Viral Hepat.

(2021)

K.A. McGlynn et al.Epidemiology of hepatocellular carcinoma

Hepatology

(2021)

C. Moreno-León et al.Cooperation Between Aflatoxin-Induced p53 Aberrations and Hepatitis B Virus in Hepatocellular Carcinoma

J. Xenobiotics

(2025)

R.W. Zeng et al.Global prevalence, clinical characteristics, surveillance, treatment allocation, and outcomes of alcohol-associated hepatocellular carcinoma

Clin. Gastroenterol. Hepatol.

(2024)

M. Ronot et al.Imaging to predict prognosis in hepatocellular carcinoma: current and future perspectives

Radiology

(2023)

M. Barcena-Varela et al.The endless sources of hepatocellular carcinoma heterogeneity

Cancers

(2021)

L.-Q. Yao et al.Clinical features of recurrence after hepatic resection for early-stage hepatocellular carcinoma and long-term survival outcomes of patients with recurrence: a multi-institutional analysis

Ann. Surg. Oncol.

(2022)

T.M. Hassanin et al.Quality of life after transcatheter arterial chemoembolization combined with radiofrequency ablation in patients with unresectable hepatocellular carcinoma compared with transcatheter arterial chemoembolization alone

Asian Pacific Journal Cancer Prevention APJCP

(2021)

H. Iwamoto et al.Hepatic arterial infusion chemotherapy for advanced hepatocellular carcinoma in the era of chemo-diversity

Clin. Mol. Hepatol.

(2023)

Y. MatsuoStereotactic body radiotherapy for hepatocellular carcinoma: a brief overview

Curr. Oncol.

(2023)

D. Sokolov et al.Differential signaling pathways in medulloblastoma: nano-biomedicine targeting non-coding epigenetics to improve current and future therapeutics

Curr. Pharm. Des.

(2024)

J. Wu et al.Radioresistance in Hepatocellular Carcinoma: Biological Bases and Therapeutic Implications

Int. J. Mol. Sci.

(2025)

K. Lohitesh et al.Resistance a major hindrance to chemotherapy in hepatocellular carcinoma: an insight

Cancer Cell Int.

(2018)

Y.-F. Chiang et al.Hinokitiol inhibits breast cancer cells in vitro stemness-progression and self-renewal with apoptosis and autophagy modulation via the CD44/Nanog/SOX2/Oct4 pathway

Int. J. Mol. Sci.

(2024)

S. Eldash et al.The intergenic type LncRNA (LINC RNA) faces in cancer with in silico scope and a directed lens to LINC00511: a step toward ncRNA precision

Noncoding RNA

(2023)

C. Zhao et al.The role of tumor microenvironment reprogramming in primary liver cancer chemotherapy resistance

Front. Oncol.

(2022)

F. Heindryckx et al.Targeting the tumor stroma in hepatocellular carcinoma

World J. Hepatol.

(2015 Feb 27)

J. Guo et al.Mechanisms of resistance to chemotherapy and radiotherapy in hepatocellular carcinoma

Transl. Cancer Res.

(2018)

S.M. Radwan et al.Beclin-1 and hypoxia-inducible factor-1α genes expression: potential biomarkers in acute leukemia patients

Cancer Biomark.

(2016)

B. Satilmis et al.Hepatocellular carcinoma tumor microenvironment and its implications in terms of anti-tumor immunity: future perspectives for new therapeutics

J. Gastrointest. Cancer

(2021)

C. Mi et al.Redefining hepatocellular carcinoma treatment: nanotechnology meets tumor immune microenvironment

J. Drug Target.

(2025)

S. Taeb et al.Role of tumor microenvironment in cancer stem cells resistance to radiotherapy

Curr. Cancer Drug Targets

(2022)

T.K.-W. Lee et al.Cancer stem cells in hepatocellular carcinoma — from origin to clinical implications

Nat. Rev. Gastroenterol. & Hepatol.

(2022)

Q. Shi et al.A Notch signaling pathway-related gene signature: Characterizing the immune microenvironment and predicting prognosis in hepatocellular carcinoma

J. Transl. Int Med

(2024 Dec)

S. Chen et al.The current status of tumor microenvironment and cancer stem cells in sorafenib resistance of hepatocellular carcinoma

Front Oncol.

(2023)

G.L. Xu et al.Upregulation of PD-L1 expression promotes epithelial-to-mesenchymal transition in sorafenib-resistant hepatocellular carcinoma cells

Gastroenterol. Rep. (Oxf. )

(2020 Oct)

J. Ning et al.The complex role of immune cells in antigen presentation and regulation of T-cell responses in hepatocellular carcinoma: progress, challenges, and future directions

Front Immunol.

(2024)

C. Sun et al.Natural killer cell dysfunction in hepatocellular carcinoma and NK cell-based immunotherapy

Acta Pharmacol. Sin.

(2015)

View more referencesView full text

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