Viruses in gastrointestinal cancers: Molecular pathogenesis, oncogenic mechanisms, and translational perspectives

Viral pathogens are one of the most significant causes of human carcinogenesis, contributing to up to 15-20 % of worldwide cancers. The gastrointestinal (GI) tract is one of the most vulnerable human organ system to virus-mediated tumorigenesis as a result of frequent exposure to viral infections and various immunological processes. The present review aims to describe the dual roles of viral infections in the development of gastrointestinal cancers (GICs), with a focus on Human Immunodeficiency Virus (HIV) and Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2). HIV represents an oncological challenge in the era of effective antiretroviral therapy (ART), where significant immune dysfunction, persistent inflammation, and gut microbiome disruption render infected patients more susceptible to various GICs. On the other hand, SARS-CoV-2 is an emerging viral pathogen whose potential role in oncogenesis remains controversial yet biologically plausible. In this context, SARS-CoV-2 tropism to the gastrointestinal tissues and its capacity to drive cytokine storms, profound dysbiosis, and immune exhaustion raise significant questions regarding its potential to act as a pro-tumorigenic factor. Discussing mechanistic insights from well-known oncogenic viral pathogens, the present review describes the direct and indirect mechanisms by which these two major viruses may affect GI tumorigenesis. Moreover, this review translates these mechanisms into clinical perspectives, underscoring implications for diagnostics, prevention, and therapeutic strategies, while highlighting urgent research priorities for long-term surveillance and biomarker discovery. It highlights the importance of continuous scientific awareness to address the increasing cancer risks presented by emerging and re-emerging viruses through bridging virology and oncology.