CAR-T cell therapy and oncolytic viruses: A synergic approach for advanced GI cancers

Gastrointestinal (GI) cancers remain a leading cause of cancer-related mortality worldwide, largely due to high recurrence rates, and limited responsiveness to existing systemic therapies. Although immunotherapy has transformed the management of several malignancies, its clinical impact in GI cancers has been comparatively modest. Chimeric antigen receptor (CAR) T-cell therapy has demonstrated remarkable efficacy in hematological malignancies but faces substantial barriers in solid tumors, including poor trafficking, limited infiltration, antigen heterogeneity, and profound tumor microenvironment-mediated immune suppression. This review aims to critically evaluate the rationale, mechanisms, and emerging evidence supporting the combination of oncolytic viruses (OVs) with CAR-T cell therapy as a novel immunotherapeutic strategy for gastrointestinal malignancies. Accumulating evidence demonstrates that OVs can enhance CAR-T cell efficacy by improving tumor antigen availability, promoting immune cell trafficking and infiltration, reversing local immunosuppression, and supporting CAR-T cell activation and persistence. Diverse OV platforms-including cytokine-armed viruses, antigen-delivering vectors, and multifunctional immunomodulatory constructs-have shown synergistic antitumor effects with CAR-T cells in preclinical GI cancer models, often resulting in durable tumor regression and immunological memory. The integration of oncolytic virotherapy with CAR-T cell therapy represents a promising avenue to overcome key limitations of adoptive cell therapy in GI cancers. While clinical translation remains in its infancy, this combinatorial strategy offers a compelling framework for the development of more effective and durable immunotherapies for solid tumors.