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Background <p>Systemic therapy for hepatocellular carcinoma (HCC) has advanced with immune checkpoint inhibitors (ICIs), yet objective response rates remain limited, and predictive markers are scarce.</p> Objective <p>This article aims to summarise the clinical value of ICI combination therapies in HCC, explain their underlying mechanisms, and outline current advances towards immune-based diagnostics through immunotyping of the tumour microenvironment (TME).</p> Methods <p>Review compiling recent phase&#xa0;III trial results and translational spatial immunology studies.</p> Results <p>Immune checkpoint inhibitor combinations targeting the PD-1/PD-L1 pathway, together with CTLA‑4 blockade or VEGF inhibition, improve overall survival in HCC compared to tyrosine kinase inhibitors (TKIs). Different ICI regimens enhance T‑cell responses, with PD-(L)1 and CTLA‑4 blockade operating through distinct mechanisms. Better responses are observed in patients with high CD8 T‑cell infiltration, whereas PD-L1 expression, tumour mutational burden (TMB), and microsatellite instability (MSI) are limited predictors in HCC. A&#xa0;TME immunotype classification (immune-enriched, compartmentalised, immune-depleted) correlates with survival under immunotherapy and can be approximated by quantifying CD8 T‑cell density and its tumour–stroma distribution.</p> Conclusion <p>Immunological characterisation of the TME in HCC can help to identify suitable candidates for immunotherapy. A&#xa0;simplified immune classification of HCC is feasible using routine CD8 immunohistochemistry and can provide additional information supporting personalised treatment strategies in HCC, such as in non-advanced disease stages.</p>

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Tumormikromilieu des hepatozellulären Karzinoms – Schlüssel zur Therapiestratifizierung von Lebertumoren

  • 期刊论文

  • 发表日期：

    2025年11月11日

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  • Alexandra Emilia Schlaak,
  • Robert Thimme,
  • Bertram Bengsch

摘要

Background

Systemic therapy for hepatocellular carcinoma (HCC) has advanced with immune checkpoint inhibitors (ICIs), yet objective response rates remain limited, and predictive markers are scarce.

Objective

This article aims to summarise the clinical value of ICI combination therapies in HCC, explain their underlying mechanisms, and outline current advances towards immune-based diagnostics through immunotyping of the tumour microenvironment (TME).

Methods

Review compiling recent phase III trial results and translational spatial immunology studies.

Results

Immune checkpoint inhibitor combinations targeting the PD-1/PD-L1 pathway, together with CTLA‑4 blockade or VEGF inhibition, improve overall survival in HCC compared to tyrosine kinase inhibitors (TKIs). Different ICI regimens enhance T‑cell responses, with PD-(L)1 and CTLA‑4 blockade operating through distinct mechanisms. Better responses are observed in patients with high CD8 T‑cell infiltration, whereas PD-L1 expression, tumour mutational burden (TMB), and microsatellite instability (MSI) are limited predictors in HCC. A TME immunotype classification (immune-enriched, compartmentalised, immune-depleted) correlates with survival under immunotherapy and can be approximated by quantifying CD8 T‑cell density and its tumour–stroma distribution.

Conclusion

Immunological characterisation of the TME in HCC can help to identify suitable candidates for immunotherapy. A simplified immune classification of HCC is feasible using routine CD8 immunohistochemistry and can provide additional information supporting personalised treatment strategies in HCC, such as in non-advanced disease stages.