Innate Antiviral Immunity as a Double-Edged Determinant of Oncolytic Virotherapy Outcomes

Abstract

Oncolytic virotherapy (OVT) has emerged as a promising cancer immunotherapy strategy that combines selective tumor cell infection and lysis with immune activation. However, clinical responses remain variable, and innate antiviral immunity is a key determinant of this variability. Type I interferon (IFN) signaling and downstream interferon-stimulated genes can restrict viral replication, limit intratumoral spread, and reduce direct oncolysis, particularly in tumors with intact or elevated antiviral programs. At the same time, these pathways can also promote therapeutic benefit by inducing inflammatory cytokines and chemokines, enhancing antigen presentation, recruiting innate and adaptive immune cells, and converting poorly inflamed tumors into more immunologically active microenvironments. This commentary discusses innate antiviral immunity as a double-edged regulator of OVT outcomes, with an emphasis on tumor-intrinsic antiviral defenses, immune priming, viral genetics, cellular context, and rational combination strategies. Reovirus is highlighted as a case study in which viral strain variation, reassortment, infection kinetics, IFN modulation, and tumor cell type may shape therapeutic outcomes. Rather than seeking maximal viral replication or maximal innate immune activation, future OVT approaches should aim to define a productive immune window that supports viral oncolysis while preserving the inflammatory signals needed for durable antitumor immunity.