Oncolytic virotherapy for cancer: biological mechanisms, clinical advances, and future perspectives

Abstract Oncolytic virotherapy has emerged as a promising cancer treatment that combines selective tumor destruction with potent stimulation of antitumor immunity. Unlike conventional therapies, oncolytic viruses (OVs) preferentially infect and replicate within malignant cells while sparing normal tissues, leading to direct tumor lysis and the release of tumor-associated antigens, pathogen-associated molecular patterns, and damage-associated molecular patterns that activate both innate and adaptive immune responses. Advances in molecular virology and genetic engineering have transformed naturally occurring viruses into programmable therapeutic platforms capable of delivering immunomodulatory payloads that enhance antitumor efficacy and remodel the tumor microenvironment. Multiple DNA- and RNA-based viral platforms, including herpes simplex virus, adenovirus, vaccinia virus, reovirus, measles virus, Newcastle disease virus, vesicular stomatitis virus, and coxsackievirus, are currently under clinical investigation, with regulatory approval of talimogene laherparepvec (T-VEC) and G47Δ providing important proof of clinical feasibility. Increasing evidence indicates that OVs can convert immunologically "cold" tumors into "hot" tumors, thereby improving responsiveness to immune checkpoint inhibitors and other therapeutic modalities. Consequently, oncolytic virotherapy has become an attractive component of combination strategies involving immunotherapy, chemotherapy, radiotherapy, targeted therapies, and cellular therapies. Nevertheless, several challenges continue to limit its broader clinical application, including antiviral immune clearance, inefficient systemic delivery, restricted intratumoral spread, tumor heterogeneity, manufacturing complexity, and the lack of robust predictive biomarkers. This review provides a comprehensive overview of the biological foundations of oncolytic virotherapy, viral engineering strategies, mechanisms of tumor selectivity, direct oncolysis, immunogenic cell death, and immune remodeling of the tumor microenvironment. It further summarizes the major oncolytic virus platforms, recent preclinical and clinical advances, emerging combination strategies, current translational challenges, and future directions expected to advance precision oncolytic virotherapy and expand its role in modern cancer treatment. Graphical Abstract Comprehensive overview of oncolytic virotherapy (OVT) from fundamental biology to clinical translation