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Targeting metalloproteases is a promising strategy to enhance immunotherapy responses by overcoming immune exclusion in hepatocellular carcinoma
  1. Marina Barcena-Varela1,
  2. Pedro Berraondo2
  1. 1Department of Oncological Sciences, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, New York, USA
  2. 2Immunology, Cima-University of Navarra, Pamplona, Spain
  1. Correspondence to Dr Marina Barcena-Varela, Department of Oncological Sciences, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, New York, 10029, USA; marina.barcena-varela{at}

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The advent of immune checkpoint inhibitors, particularly monoclonal antibodies (mAbs) that target the programmed cell death protein 1 (PD-1) or its ligand (PD-L1), has revolutionised cancer treatment across various malignancies. Despite this groundbreaking progress, a considerable cohort of patients fails to derive benefit from anti-PD(L)1 mAb therapy due to primary and secondary resistance mechanisms. The percentage of patients who respond to these treatments varies among different tumour types, ranging from 40% in more sensitive tumours, like metastatic melanoma, to virtually zero in less sensitive tumours such as glioblastoma.1 Hepatocellular carcinoma (HCC), one of the deadliest solid tumours, emerges as a moderately sensitive tumour, where monotherapy with anti-PD(L)1 agents demonstrates a response in only about 15% of cases.2 These encouraging yet constrained clinical outcomes have elevated immunotherapy to a pivotal status in clinical practice, instigating evaluations of combinatory approaches with other agents alongside anti-PD(L)1 mAbs to circumvent resistance mechanisms constraining monotherapies. Among the various combinations evaluated in clinical trials, those that have stood out for their positive results include the combination of anti-PD(L)1 mAb with the antiangiogenic agent, bevacizumab3 or with other immune checkpoint inhibitor, anti-CTLA-4 mAb,4 becoming the first-line systemic treatment options for HCC patients.

However, new therapeutic targets are necessary …

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  • Contributors Both authors contributed to the design and writing of the commentary.

  • Funding MB-V was supported by Cholangiocarcinoma Foundation (CCF) Research Fellowship, and by the Postdoctoral Fellowship Grant from Ramon Areces Foundation. PB was supported by Instituto de Salud Carlos III (PI22/00147) co-financed by Fondos Feder, Gobierno de Navarra Proyecto ARNMUNE Ref: 0011–1411-2023, and a 2022 Leonardo Grant for Researchers and Cultural Creators, BBVA Foundation.

  • Competing interests None declared.

  • Provenance and peer review Commissioned; internally peer-reviewed.

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