Dynamics modeling and synergistic mechanisms of oncolytic virus-bortezomib combination therapy

For cancer treatment, the combination therapy of oncolytic virus (OV) and bortezomib, a proteasome inhibitor, is a highly worthy research problem. We develop a nonlinear mathematical model that captures the dynamics of uninfected and infected tumor cells, free oncolytic virus particles, bortezomib and natural killer (NK) cells. We consider bortezomib administered periodically and integrate the bortezomib administration functions into the model. We explore the strategies for oncolytic virotherapy, an impulsive dose, where one viral dose is administered at several successive time points. We derive the OV infection threshold, [Formula: see text], which determines whether the viral infection will persist ([Formula: see text] or be eliminated ([Formula: see text]). We theoretically demonstrate that periodic injections of bortezomib and limited pulse injections of OV can eliminate tumor cells. Numerical simulations show the uninfected tumor cell population is significantly reduced when [Formula: see text], and the overall therapeutic efficacy of virotherapy shows a substantial improvement compared to cases where [Formula: see text]. Through global sensitivity analysis, we evaluate the impact of both OV- and bortezomib-related parameters on treatment outcomes. The results indicate that OV-related parameters substantially influence virotherapy efficacy, whereas bortezomib-related parameters have minimal impact on overall treatment success but do significantly affect the equilibrium level of uninfected tumor cells. Our results reveal how OV-Bortezomib combination therapy works synergistically, guiding better cancer treatment design.