Employing the Oncolytic Vesicular Stomatitis Virus in Cancer Virotherapy: Resistance and Clinical Considerations.

Vesicular Stomatitis Virus (VSV) has emerged as a promising candidate for various clinical applications, including vaccine development, virus pseudotyping, and gene delivery. Its broad host range, ease of propagation, and lack of pre-existing immunity in humans make it ideal for therapeutic use. VSV's potential as an oncolytic virus has garnered attention; however, resistance to VSV-mediated oncolysis has been observed in some cell lines and tumor types, limiting its effectiveness. This review provides a detailed analysis of recent advances in VSV-based oncolysis, focusing on resistance mechanisms such as sustained type-I IFN signaling, upregulation of ISGs, immune cell activation, the tumor microenvironment (TME), and tumor-intrinsic factors. Strategies to overcome resistance include enhancing viral oncoselectivity, inhibiting IFN responses, modulating the TME, and combining VSV with chemotherapies, radiation, and immune checkpoint inhibitors. Several VSV-based phase I/II clinical trials show promise; however, addressing resistance and developing novel strategies to enhance therapeutic efficacy are essential for realizing the full potential of VSV oncolytic virotherapy. Future research should focus on patient-specific approaches, as tumor heterogeneity implies varying resistance mechanisms. Personalized treatments tailored to tumor molecular profiles, along with identifying biomarkers predictive of resistance to VSV oncolysis, will enhance patient selection and enable more effective, individualized VSV-based therapies.