Bridging mechanism and clinic: unlocking the full potential of oncolytic virus-based immunotherapy

Oncolytic viruses (OVs) have emerged as a distinctive class of cancer therapeutics capable of coupling direct tumor cell lysis with broad immune activation, thereby reshaping antitumor immunity beyond the capacities of conventional modalities. Despite substantial progress, the clinical translation of OVs remains constrained by challenges such as inefficient delivery, restricted tumor selectivity, premature immune clearance and safety concerns, all of which collectively limit therapeutic efficacy. Recent advances in genetic engineering, viral retargeting and high-dimensional profiling technologies have begun to clarify the molecular and microenvironmental determinants of OV tropism and activity, providing new opportunities to optimize OV design. In this review, we synthesize current OV classifications, mechanisms of action and clinical developments, and highlight emerging innovations spanning synthetic engineering, targeted delivery platforms and combination therapy strategies—including those integrating OVs with immunotherapies, targeted agents and conventional modalities—to amplify therapeutic potency and overcome resistance. Together, these perspectives provide an integrated framework for understanding OV biology, underscore the need to address persistent barriers to safe and effective clinical deployment, and outline key priorities for advancing OVs toward their potential as a foundational component of next-generation, personalized cancer immunotherapy.