Integrating Oncolytic Virus Engineering and Delivery Strategies for Enhanced Cancer Virotherapy

Abstract

Oncolytic virotherapy represents a compelling strategy for cancer immunotherapy, integrating direct tumor cell lysis with the activation of systemic antitumor immunity. Despite its therapeutic promise, clinical translation remains fundamentally limited by inefficient viral delivery, rapid immune clearance, and the highly immunosuppressive tumor microenvironment (TME). These barriers have shifted the field from virus-centric optimization alone toward integrated engineering strategies that jointly modulate viral design, delivery platforms (e.g., cell-based, microbial, or engineered systems), and host immunity. This review examines how genetic engineering has improved the potency and selectivity of oncolytic viruses (OVs) under local administration, and how delivery platforms have expanded these capabilities by enabling viral protection, controlled release, and microenvironmental modulation. In addition, emerging strategies for systemic delivery, including molecular camouflage, carrier-mediated transport, and biomimetic nanosystems designed to overcome immune neutralization and enhance tumor targeting, are discussed. Finally, we outline key design principles for the next generation of oncolytic virotherapy, emphasizing the need for spatiotemporally controlled, immune-integrated delivery systems that can support safe and effective systemic treatment.

Keywords

local delivery / oncolytic virus / systemic delivery

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