Oncolytic viruses (OVs) are emerging as promising cancer immunotherapeutic agents due to their cancer-directed oncolysis and ability to induce potent and durable anticancer immune responses. They have shown encouraging results even in tumors that are resistant to conventional therapies. However, the therapeutic efficacy of OVs is hindered by antiviral immune responses that eliminate OVs before they reach their target site and the tumor stroma, limiting intratumoral virus spread in the tumor microenvironment (TME). To address these challenges, various strategies have been developed to shield OVs from immunosurveillance by loading viruses onto/into cellular carriers, extracellular vesicles, liposomes, and nanoparticles. Despite notable improvements in viral shielding and targeting strategies, inefficient intratumoral viral penetration remains a critical obstacle. In the TME, the tumor stroma accounts for 90% of the entire tumor mass, comprising non-cancerous cells and extracellular matrix. Since OVs are engineered to target only cancer cells, their cytolytic efficacy is counteracted by the tumor stroma. Therefore, innovative approaches are necessary to enhance the penetration of viruses within tumors, thereby increasing the efficacy of oncolytic virotherapy. This review aims to provide a comprehensive overview of OVs in terms of clinical applications, successes, and limitations, while also discussing future directions for enhancing the targeted delivery and intratumoral penetration of OVs.

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