Hepatocellular carcinoma organoids enable drug discovery and combination therapy across heterogeneous tumors

  • Cell Rep. 2026 Sep 22;45(9):117895. doi: 10.1016/j.celrep.2026.117895.
Sandro Nuciforo  1 ,  Lauriane Blukacz  2 ,  Marie-Anne Heusler  3 ,  Tijmen H Booij  4 ,  Lukas Kübler  2 ,  Fredrik Trulsson  5 ,  Tuyana Boldanova  2 ,  Xueya Wang  2 ,  Sylvia Ketterer  2 ,  Matthias S Matter  6 ,  Christian U Stirnimann  4 ,  Stefan Wieland  7 ,  Markus H Heim  8
Affiliations
  • 1. Department of Biomedicine, Hepatology Laboratory, University of Basel, University Hospital Basel, 4031 Basel, Switzerland. Electronic address: [email protected].
  • 2. Department of Biomedicine, Hepatology Laboratory, University of Basel, University Hospital Basel, 4031 Basel, Switzerland.
  • 3. Department of Biomedicine, Hepatology Laboratory, University of Basel, University Hospital Basel, 4031 Basel, Switzerland; University Digestive Health Care Center Basel - Clarunis, 4002 Basel, Switzerland.
  • 4. NEXUS Personalized Health Technologies, ETH Zurich, 8093 Zurich, Switzerland.
  • 5. Department of Biomedicine, Hepatology Laboratory, University of Basel, University Hospital Basel, 4031 Basel, Switzerland; sciCORE Center for Scientific Computing and Center for Data Analytics, University of Basel, 4056 Basel, Switzerland.
  • 6. Institute of Pathology, University Hospital Basel, 4031 Basel, Switzerland.
  • 7. Department of Biomedicine, Hepatology Laboratory, University of Basel, University Hospital Basel, 4031 Basel, Switzerland; Department of Immunology and Microbiology, The Scripps Research Institute, La Jolla, CA 92037, USA.
  • 8. Department of Biomedicine, Hepatology Laboratory, University of Basel, University Hospital Basel, 4031 Basel, Switzerland; University Digestive Health Care Center Basel - Clarunis, 4002 Basel, Switzerland. Electronic address: [email protected].
PMID: 42636109 DOI: 10.1016/j.celrep.2026.117895
Abstract

Hepatocellular carcinoma (HCC) remains a leading cause of Cancer mortality, with limited therapeutic options and poor clinical outcomes. Tumor heterogeneity is a defining feature of HCC and a major barrier to effective treatment. To address this, we established a biobank of patient-derived HCC organoids generated from diagnostic biopsies, capturing the diversity of clinical features across disease stages. Using a high-throughput phenotypic screening platform, we tested more than 1,600 compounds and identified multiple agents with strong antitumor activity, including candidates suitable for drug repurposing. To further improve therapeutic responses, we systematically evaluated rationally designed doublet and triplet combinations anchored on regorafenib. Several combinations showed enhanced efficacy across HCCOs while maintaining selectivity over non-tumoral cells. In vivo validation of a selected triplet confirmed improved tumor control and tolerability. Together, these findings establish patient-derived organoids as a scalable platform for functional drug discovery and support combination strategies improving response across heterogeneous HCC.

Keywords
CP: cancer; combination therapy; drug discovery; liver cancer; patient-derived organoids; phenotypic screening.
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