Advanced hepatocellular carcinoma (HCC), the fate of a majority of HCC patients, is a lethal disease. Systemic therapy using tyrosine kinase inhibitors (TKI) or, since November 2020, the combination of a TKI and an immune checkpoint inhibitor (ICI) only provides a short survival benefit for only a subset of patients and exhibits substantial adverse effects. New treatment options using combination therapies are an urgent unmet clinical need. Deubiquitinases (DUBs) are a large family of druggable enzymes that control oncoproteins or their regulators. We showed that inhibition of the DUB UCHL1 in vitro strongly sensitizes HCC cells to the clinically used TKIs Sorafenib. This initiated the imaging-based in vitro screening approach presented here in which the effect of DUB targeting in combination with TKIs or ICIs is scored on HCC cell lines or patient-derived cocultures containing patient HCC and immune cells. In vivo validation data on the most potent drug combinations, supported by analysis of changes in the ubiquitome or in tumor cell antigen presentation, may have substantial impact by initiating new DUB inhibitor development and new clinical trials. Additionally, the immune-competent in vitro patient cell coculture test will form a basis for developing a new prognostic test tool of use in the clinic.