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Giulia Francesca Manfredi,1,2 Ciro Celsa,1,3,4 Chloe John,1 Charlotte Jones,1 Nicole Acuti,1 Bernhard Scheiner,5 Claudia Angela Maria Fulgenzi,1,6 James Korolewicz,1 Matthias Pinter,5 Alessandra Gennari,7 Francesco A Mauri,1 Mario Pirisi,2,8 Rosalba Minisini,2 Federica Vincenzi,2 Michela Burlone,8 Cristina Rigamonti,2,8 Matteo Donadon,9,10 Giuseppe Cabibbo,3 Antonio D’Alessio,1,7 David James Pinato1,7 1Department of Surgery & Cancer, Imperial College London, Hammersmith Hospital, London, UK; 2Department of Translational Medicine, Università Del Piemonte Orientale, Novara, Italy; 3Section of Gastroenterology & Hepatology, Department of Health Promotion, Mother and Child Care, Internal Medicine and Medical Specialties, PROMISE, University of Palermo, Palermo, Italy; 4Department of Surgical, Oncological and Oral Sciences (Di.chir.on.s.), University of Palermo, Palermo, Italy; 5Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria; 6Department of Medical Oncology, University Campus Bio-Medico of Rome, Rome, Italy; 7Division of Oncology, Department of Translational Medicine, University of Piemonte Orientale, Novara, Italy; 8Division of Internal Medicine, AOU Maggiore della Carità, Novara, Italy; 9Department of Health Science, Università Del Piemonte Orientale, Novara, Italy; 10Department of Surgery, University Maggiore Hospital della Carità, Novara, ItalyCorrespondence: David James Pinato, Clinical Senior Lecturer and Consultant in Medical Oncology, Imperial College London Hammersmith Campus, Du Cane Road, London, W12 0HS, UK, Tel +44 020 83833720, Email david.pinato@imperial.ac.ukAbstract: Systemic treatment for advanced hepatocellular carcinoma (HCC) has been revolutionized over the last few years following the approval of immune checkpoint inhibitors (ICI). Despite the promising survival extension seen with ICI combination regimens, responses are not universally seen and the optimal partner for programmed cell death 1 pathway inhibitors remains to be identified. Even fewer encouraging results have been demonstrated with ICI used for monotherapy. Several mechanisms of resistance have been described so far, involving characteristics of cancer cells (intrinsic mechanisms) and of the surrounding tumor microenvironment (extrinsic mechanisms). Factors related to therapy may also contribute to the development of resistance. Increasing research efforts are being dedicated to the discovery of novel approaches and targets to overcome resistance, some of which may be introduced into clinic in the future. Herein we describe a selection of resistance mechanisms that have been involved in impairing response to ICI and propose potential therapeutic approaches to overcome resistance.Keywords: immune checkpoint inhibitors, liver cancer, recurrence, tumor microenvironment