Regulatory T Cells in Hepatocellular Carcinoma: Spatial Niches, Biomarkers, and Clinical Implications

Liapopoulos, Dimitris; Sarantis, Panagiotis; Zogas, Georgios; Trifylli, Eleni-Myrto; Bousou, Thaleia-Eleftheria; Kamitaki, Konstantina; Anastasiou, Ioanna A.; Kokkali, Stefania; Mavromatis, Sotiris; Koustas, Evangelos; Elefsiniotis, Ioannis; Biniari, Theodora; Karamouzis, Michalis V.

doi:10.3390/ijms27104630

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Regulatory T Cells in Hepatocellular Carcinoma: Spatial Niches, Biomarkers, and Clinical Implications

by

Dimitris Liapopoulos

^1,2,

Panagiotis Sarantis

^3,4,5,*

,

Georgios Zogas

⁴,

Eleni-Myrto Trifylli

⁶,

Thaleia-Eleftheria Bousou

⁷,

Konstantina Kamitaki

⁸,

Ioanna A. Anastasiou

⁹

,

Stefania Kokkali

¹⁰,

Sotiris Mavromatis

¹,

Evangelos Koustas

¹¹,

Ioannis Elefsiniotis

⁴

,

Theodora Biniari

¹ and

Michalis V. Karamouzis

^4,5

¹

Biopathological Laboratory, General and Oncology Hospital “Agioi Anargyroi”, National and Kapodistrian University of Athens, Timiou Stavrou 14, 145 64 Kifisia, Greece

²

Biopathological Laboratory, Athens Medical Group, Psychiko Clinic, Antersen 1, 115 25 Psychiko, Greece

³

Department of Biological Chemistry, Medical School, National and Kapodistrian University of Athens, Mikras Asias 75, 115 27 Athens, Greece

⁴

University Clinic of Internal Medicine, General and Oncology Hospital “Agioi Anargyroi”, National and Kapodistrian University of Athens, Timiou Stavrou 14, 145 64 Kifisia, Greece

⁵

Institute of Molecular Medicine and Biomedical Research, 115 27 Athens, Greece

⁶

Second Department of Internal Medicine-GI-Liver Unit, General Hospital ‘Hippokratio’, Medical School, National and Kapodistrian University of Athens, Vasilissis Sofias 114, 115 27 Athens, Greece

⁷

First Department of Internal Medicine, Laiko General Hospital, Agiou Thoma 17, 115 27 Athens, Greece

⁸

Blood Bank, General and Oncology Hospital “Agioi Anargyroi”, National and Kapodistrian University of Athens, Timiou Stavrou 14, 145 64 Kifisia, Greece

⁹

Department of Pharmacology, Medical School, National and Kapodistrian University of Athens, Mikras Asias 75, 115 27 Athens, Greece

¹⁰

Oncology Unit, Second Department of Medicine, University of Athens, Hippocratio General Hospital of Athens, 115 27 Athens, Greece

¹¹

Oncology Department, General Hospital Evangelismos, Ipsilantou 45-47, 106 76 Athens, Greece

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Author to whom correspondence should be addressed.

Int. J. Mol. Sci. 2026, 27(10), 4630; https://doi.org/10.3390/ijms27104630

Submission received: 11 March 2026 / Revised: 15 May 2026 / Accepted: 18 May 2026 / Published: 21 May 2026

(This article belongs to the Special Issue Next-Gen Biomarkers for Cancer Immunotherapy)

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Abstract

Hepatocellular carcinoma (HCC) is a leading cause of cancer mortality worldwide, increasingly driven by metabolic dysfunction-associated steatotic liver disease alongside viral and alcohol-related cirrhosis. The tolerogenic immune environment of the liver enables tumor immune escape, with regulatory T cells (Tregs) playing a central role. This review synthesizes human-focused evidence (tissues, blood, clinical cohorts, and single-cell/spatial studies) through September 2025 to define how Tregs are recruited, maintained, and functionally deployed in HCC. Across datasets, intratumoral effector-like Tregs (eTregs) expressing ICOS, CTLA-4, CCR8, and CD39/CD73 accumulate within tumors and co-localize with exhausted cytotoxic PD-1^hi CD8⁺ T cells and suppressive myeloid cells. Recruitment is driven mainly by CCL20–CCR6 and CCL22/CCL17–CCR4 signaling, while CCR8 marks highly suppressive tumor-resident Tregs. Their persistence is supported by TGF-β, IL-10, IL-35, adenosine signaling, IL-2 sequestration, and metabolic adaptation. Spatial biomarkers, including ICOS⁺/CCR8⁺ eTreg density and CD8:Treg ratios, associate with prognosis and emerging immunotherapy responses. Etiology further shapes immune architecture: HBV-related HCC often forms Treg-exhausted T-cell niches around viral antigens, whereas MASLD/MASH promotes stromal and metabolic barriers that may reduce PD-(L)1 efficacy. Current treatments (PD-(L)1 blockade with anti-VEGF or CTLA-4, and some TKIs) intersect with Treg biology, while emerging strategies targeting CCR8, CCR4, ICOS, or the adenosine pathway aim to selectively disrupt intratumoral eTreg networks. This review underscores that an etiology-aware, spatial-biomarker framework may guide the integration of selective Treg targeting with PD-(L)1-based therapies in HCC.

Keywords: regulatory T cells; hepatocellular carcinoma; tumor microenvironment; CCR8; ICOS; adenosine pathway; spatial biomarkers; immunotherapy

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MDPI and ACS Style

Liapopoulos, D.; Sarantis, P.; Zogas, G.; Trifylli, E.-M.; Bousou, T.-E.; Kamitaki, K.; Anastasiou, I.A.; Kokkali, S.; Mavromatis, S.; Koustas, E.; et al. Regulatory T Cells in Hepatocellular Carcinoma: Spatial Niches, Biomarkers, and Clinical Implications. Int. J. Mol. Sci. 2026, 27, 4630. https://doi.org/10.3390/ijms27104630

AMA Style

Liapopoulos D, Sarantis P, Zogas G, Trifylli E-M, Bousou T-E, Kamitaki K, Anastasiou IA, Kokkali S, Mavromatis S, Koustas E, et al. Regulatory T Cells in Hepatocellular Carcinoma: Spatial Niches, Biomarkers, and Clinical Implications. International Journal of Molecular Sciences. 2026; 27(10):4630. https://doi.org/10.3390/ijms27104630

Chicago/Turabian Style

Liapopoulos, Dimitris, Panagiotis Sarantis, Georgios Zogas, Eleni-Myrto Trifylli, Thaleia-Eleftheria Bousou, Konstantina Kamitaki, Ioanna A. Anastasiou, Stefania Kokkali, Sotiris Mavromatis, Evangelos Koustas, and et al. 2026. "Regulatory T Cells in Hepatocellular Carcinoma: Spatial Niches, Biomarkers, and Clinical Implications" International Journal of Molecular Sciences 27, no. 10: 4630. https://doi.org/10.3390/ijms27104630

APA Style

Liapopoulos, D., Sarantis, P., Zogas, G., Trifylli, E.-M., Bousou, T.-E., Kamitaki, K., Anastasiou, I. A., Kokkali, S., Mavromatis, S., Koustas, E., Elefsiniotis, I., Biniari, T., & Karamouzis, M. V. (2026). Regulatory T Cells in Hepatocellular Carcinoma: Spatial Niches, Biomarkers, and Clinical Implications. International Journal of Molecular Sciences, 27(10), 4630. https://doi.org/10.3390/ijms27104630

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Regulatory T Cells in Hepatocellular Carcinoma: Spatial Niches, Biomarkers, and Clinical Implications

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