Killing to cure: harnessing poxvirus-driven cell death for viral immunotherapy

Oncolytic virotherapy represents a promising frontier in cancer immunotherapy, leveraging the ability of oncolytic viruses (OVs) to selectively replicate within tumour cells and induce antitumour immunity. In this review, we focus on the clinical development of oncolytic poxviruses and propose that understanding fundamental mechanisms of poxvirus-induced cell death can inform rational clinical development strategies that may avoid challenges and improve outcomes in viral immunotherapy. We discuss the development of Olvimulogene nanivacirepvec (Olvi-Vec), Pexastimogene devacirepvec (Pexa-Vec), and other candidates; the basic biology of poxviruses; their manipulation of host antiviral defences; and the pathways of regulated cell death they can induce, including apoptosis, necroptosis, pyroptosis, and ferroptosis. We examine the potential for optimising oncolysis through targeted genetic modification and combination therapy, with the aim of enhancing the immunogenicity of cell death to overcome the immunosuppressive tumour microenvironment and to enhance adaptive antitumour immune responses.