Hepatocellular carcinoma (HCC), or primary liver cancer, is one of the leading causes of mortality worldwide. Liver cirrhosis, characterized by deposition of excessive extracellular matrix (ECM) secreted by hepatic stellate cells (HSCs), is the major risk factor of HCC development. Although anti-fibrotic therapies hold great promise in the treatment of HCC, conventional non-animal models lack the complexity of the tumor microenvironment, especially its ECM component, driving efforts to develop more representative platforms. In this context, we bioengineered HCC spheroids by co-culturing human HCC cells (HepG2) with human HSCs (LX-2) in different ratios using a soft-embossed microwell array platform. HCC spheroids, depending on their exact composition, displayed typical HCC features, such as the presence of an ECM-rich capsule, as revealed by immunostaining of collagen type I on intact spheroids after tissue clearing. We hypothesized that the presence of this capsule, which is involved in several stages of tumor progression, could act as a ‘protective barrier’ that regulates the penetration and delivery of therapeutic agents. This hypothesis was confirmed using our bioengineered HCC spheroids, in which the combined presence of HSCs and ECM hinders the penetration and therapeutic efficacy of a model chemotherapeutics (doxorubicin). This could be improved by concomitant enzymatic degradation of the ECM-rich capsule. Altogether, we propose our HCC model as a relevant platform to study tumor-tumor microenvironment interactions, gain mechanistic insights into HCC, identify novel therapeutic targets and evaluate (combination) therapies targeting tumor-tumor microenvironment while integrating ECM degradation with the (targeted) delivery of therapeutic agents.