Oncolytic Viruses as a Novel Therapeutic Approach for Colorectal Cancer: Mechanisms, Current Advances, and Future Directions

Abstract

This review provides an updated overview of oncolytic virotherapy as a promising therapeutic strategy for colorectal cancer (CRC), focusing on six key viral platforms: adenovirus, herpes simplex virus (HSV), reovirus, vesicular stomatitis virus (VSV), vaccinia virus (VV), and measles virus (MV). These viruses exhibit tumor-selective replication and exert their effects through mechanisms such as direct oncolysis, the delivery of immunostimulatory genes (e.g., IL-12, IL-15, GM-CSF), the activation of innate and adaptive immune responses, and the remodeling of the tumor microenvironment. Preclinical and early clinical studies suggest that oncolytic viruses can enhance the efficacy of existing treatments, particularly in immunologically "cold" tumors such as microsatellite stable CRC, when used in combination with chemotherapy or immune checkpoint inhibitors. Despite encouraging results, several challenges remain, including antiviral immune clearance, tumor heterogeneity, and limitations in systemic delivery. Current research focuses on improving viral engineering, enhancing tumor targeting, and designing combinatorial strategies to overcome resistance and maximize clinical benefits. Overall, oncolytic viruses represent a versatile and evolving therapeutic class with the potential to address unmet clinical needs in CRC.

Keywords: adenovirus; colorectal cancer; immunotherapy; oncolytic viruses; virotherapy.

Figure 1

Schematic representation of the leading oncolytic virus platforms investigated for colorectal cancer (CRC) and their mechanisms of action. Adenoviruses (AD) selectively replicate in tumor cells and deliver therapeutic genes such as IL-15, GM-CSF, and TRAIL, promoting direct lysis and immune activation. Herpes simplex viruses (HSV) induce tumor cell death and express immunomodulatory molecules such as IL-12, CXCL11, and anti–PD–1 antibodies, facilitating CD8⁺ T cell recruitment and the remodeling of the tumor microenvironment (TME). Reoviruses preferentially infect KRAS-mutant cells and activate innate immunity via TLR3, leading to apoptotic tumor cell death. Vesicular stomatitis viruses (VSV) trigger apoptosis through their matrix protein and are armed with IL-15 to enhance CD8⁺ and NK cell responses while modulating interferon signaling. Vaccinia viruses (VV) act effectively in hypoxic tumor areas and express a range of cytokines, including IL-12, IL-9, IL-23, and TRAIL, contributing to immune cell infiltration and the suppression of tumor-promoting signals. Measles viruses (MV) target tumor-initiating cells expressing uPAR or CD133 and are often engineered to express IL-12, inducing durable anti-tumor immune responses and long-term memory. (Created in https://BioRender.com. Accessed on 13 May 2025).