LAUSR

Simple Summary Oncolytic viruses (OVs) are the most innovative and promising class of intratumoral immunotherapies. The broad immunogenic landscape of skin cancer, accessible to intralesional infusion and available for direct response assessment, seems to be an ideal platform to expand the role of OVs. The established efficacy of immune checkpoint inhibitors (ICIs) in this field and their hypothetical synergy with OVs have generated expectations for their combined use beyond the current immunotherapy achievements. Despite the recent negative phase III results of the MASTERKEY-265 trial for the combination of T-VEC plus pembrolizumab, such projects, including different ICIs and various natural or genetically modified OVs, continue to attract considerable interest, with numerous clinical trials underway for all the subtypes of skin cancer. To date, the majority of studies confirm the safety of tested OVs in patients with advanced skin cancers but cannot clearly prove whether these viral agents add any therapeutic benefit in the standard ICI-based approach. The aim of this overview is to present the main findings related to the examined OV-containing regimens at pre-clinical and clinical levels, and to discuss the previous failures as well as the future perspectives of oncolytic virotherapy. Abstract Despite the durable remissions induced by ICIs and targeted therapies in advanced melanoma and non-melanoma skin cancers, both subtypes usually relapse. Many systematic therapies have been tested to increase efficacy and delay relapse in ICIs, but their success has been limited. Due the feasibility of this approach, skin cancers have become the ideal platform for intralesional infusions of many novel agents, including oncolytic viruses (OVs). Talimogene laherparepvec (T-VEC) was the first FDA-approved OV for the treatment of unresectable melanoma and this virus opened up further potential for the use of this class of agents, especially in combination with ICIs, in order to achieve deeper and longer immune-mediated responses. However, the recently announced phase III MASTERKEY-265 trial was not able to confirm that the addition of T-VEC to pembrolizumab treatment improves progression-free or overall survival over the use of pembrolizumab alone. Despite these results, numerous studies are currently active, evaluating T-VEC and several other OVs as monotherapies or in regimens with ICIs in different subtypes of skin cancer. This overview provides a comprehensive update on the evolution status of all available OVs in melanoma and non-melanoma skin cancers and summarizes the more interesting preclinical findings, the latest clinical evidence, and the future insights in relation to the expected selective incorporation of some of these OVs into oncological practice.