Asymmetric drug effects drive near-extinction cancer cell oscillations in transgenic oncolytic virotherapy: A modelling study

A bstract Oncolytic viruses provide cancer therapy using replication-competent viruses that selectively infect and lyse tumour cells. Their tumour-specific replication also enables the delivery of targeted, virus-encoded gene products, such as enzymes that activate prodrugs. This dual functionality offers the potential for synergistic effects by combining direct oncolysis with localised drug activation. The interplay between infection, replication, lysis, and gene product delivery remains poorly understood. Here, we introduce a spatially structured, multi-patch model of cancer cells infected by an oncolytic virus engineered to deliver a prodrug-activating enzyme. The spatial system is first represented as a microscopic model and subsequently reduced via spectral dimension reduction techniques. This reduction yields an ordinary differential equation model for a set of coarse-grained variables, which we analyze both without the transgene (OV model) and with the transgene (TOV model). For each case, we compute the basic reproduction number, R 0 , which determines the conditions for viral spread. Both models exhibit three regimes via transcritical bifurcations: (i) R 0 < 0, extinction of both cancer and infected cells; (ii) 0 1, coexistence as a stable node or as a focus. The TOV model, as a difference form the OV model, can undergo periodic oscillations arising from a Hopf–Andronov bifurcation. Notably, oscillation amplitudes can be controlled such that cancer cells largely decrease when drug-induced death is stronger in non-infected cells than in infected ones, enabling effective cancer cells killing while maintaining viral replication and prodrug activation. The qualitative behaviour of the coarse-grained model is shown to be preserved in both the microscopic and spatially explicit models.