Oncolytic Therapy: Delivery System and New Therapeutic Strategies for Cancer

Oncolytic virotherapy is an emerging cancer immunotherapy that combines selective tumor cell lysis with activation of systemic antitumor immunity. Various DNA- and RNA-based oncolytic viruses (OVs) have demonstrated favorable safety profiles and therapeutic activity across different malignancies. Despite these advancements, clinical efficacy remains inconsistent because of several biological barriers, including rapid immune clearance, insufficient tumor targeting, limited intratumoral spread, and the immunosuppressive tumor microenvironment (TME). In this review, we examine the key mechanisms of OV infection, tumor selectivity, and virus-induced antitumor immune responses. It also explores the factors that limit therapeutic efficacy, particularly host antiviral immunity, structural barriers within solid tumors, and the immunosuppressive networks in the TME. To address these challenges, a range of strategies have been developed, with a focus on optimizing viral delivery. Current approaches, such as cell-based carriers, extracellular vesicle-mediated transport, and nanomaterial-assisted delivery systems, aim to enhance tumor targeting, protect viral integrity, and improve intratumoral distribution. Additionally, combination therapies designed to enhance antitumor immunity and reshape the TME are outlined, including immune checkpoint blockade, chemoradiotherapy, and metabolic modulation. Collectively, these advancements transform OVs from standalone cytolytic agents into adaptable immunotherapeutic platforms, with their effectiveness determined by the delivery method, microenvironmental conditions, and therapeutic integration.