Oncolytic viruses as cancer therapeutics: From mechanistic insights to clinical translation.

Oncolytic virotherapy is a therapeutic approach that leverages genetically engineered or naturally occurring viruses to selectively target and destroy cancer cells while sparing normal tissues. This review provides an overview of the mechanisms of action by oncolytic viruses (OVs), including direct oncolysis, immune activation, and tumor microenvironment (TME) modulation. Despite significant progress, challenges such as immune resistance, tumor evasion mechanisms, and delivery barriers continue to limit the efficacy of OVs. To address these obstacles, recent advances in OV engineering have focused on arming viruses with immunomodulatory molecules, utilizing tumor-specific promoters, and employing CRISPR-based genome editing. Emerging strategies, such as dual-targeting OVs and viral enhancer drugs, have demonstrated promising potential in preclinical and clinical settings. This review also highlights findings from recent clinical trials, underscoring the translational challenges in scaling OVs for widespread therapeutic application. By exploring these innovations and their implications, we aim to shed light on the future directions of oncolytic virotherapy and its transformative potential in cancer treatment.