Cracking the shield: oncolytic viruses versus the tumor-immune fortress

Oncolytic viruses (OVs) have emerged as a promising cancer therapy due to their natural selectivity to replicate in and destroy cancer cells. However, despite encouraging preclinical and early clinical outcomes, the therapeutic efficacy of OVs in solid tumors remains limited. Recently, OVs have been genetically modified to enhance tumor specificity, promote antitumor immune activation, and overcome barriers imposed by the tumor microenvironment (TME). Hepatocellular carcinoma presents a uniquely challenging solid tumor microenvironment for oncolytic virotherapy, characterized by dense fibrotic stroma, potent hepatic immune clearance, and immunosuppressive signaling that collectively limit viral delivery, intratumoral spread, and therapeutic efficacy. The review provides an updated overview of clinical and preclinical studies of naturally occurring and engineered OVs, with a particular focus on the biological and translational challenges that restrict their effectiveness in HCC. In addition, it highlights the strategies developed to overcome delivery barriers, immune clearance, and tumor heterogeneity, which represent key obstacles to durable therapeutic responses. Strategies such as stromal targeting, hypoxia-adapted constructs, and the use of 3D organoid models as mimic platforms to evaluate delivery and therapeutic strategies are also discussed. Finally, this review aims to integrate recent advances in viral engineering, immune modulation, and organoid models, and critically evaluates how these approaches, together with emerging clinical trial data, can inform the rational design of next-generation oncolytic viruses.