A framework for the rational design of oncolytic viruses: A holistic perspective considering the tumour microenvironment

Oncolytic viruses have played a pioneering role in establishing immunotherapies as the next generation of anti-cancer medicines. Recent works have highlighted the impact the tumour microenvironment has on the efficacy of immunotherapies like oncolytic viruses, as well as the ability of oncolytic viruses to modulate and reconfigure this microenvironment. Within this review, we examine the vast and increasing evidence highlighting the pivotal role of tumour microenvironment in dictating oncolytic virotherapy efficacy, while also discussing potential avenues for the future development of oncolytic viruses. Following introductions to commonly used oncolytic viruses and components of the tumour microenvironment, we highlight recent research investigating their reciprocal relationships. Finally, innovations in 3D modelling to reconstitute the tumour microenvironment ex vivo are discussed, followed by examination of successful case studies in which tumour microenvironment dynamics have informed the rational design of successful and tailored oncolytic viruses. Through this, we provide evidence that substantial tumour heterogeneity amongst patients and tumour types significantly impedes effective oncolytic virotherapy, thus we suggest that consideration of each unique tumour microenvironment’s dynamics is critical for the design of functional and efficacious oncolytic virotherapy – both as a monotherapy or in combination with other cancer therapies.