Abstract
Oncolytic viruses selectively target cancer cells, which is beneficial for combination therapy with immune checkpoint-targeted therapies or for direct oncolysis. Among the increasing number of cancer cases, colorectal cancer (CRC) is one of the leading causes of death. Many studies have shown that mammalian-origin rotavirus can be repurposed as an oncolytic virus for CRC. Rotaviruses can evade inflammatory immune responses upon infection and exhibit specificity for cancer cells, a highly suitable characteristic for oncolytic viruses. In this study, we aim to explore the experimental infection of pigeon rotavirus A (pRVA), an infectious disease that causes young pigeon disease syndrome (YPDS) in pigeons. Here, we report the first case of an avian-origin rotavirus as an oncolytic virus against colorectal cancer cells, HT29 and Caco2. The pRVA showed higher infectivity and selectivity in HT29 cells than in Caco2 cells, with evident cytopathic effects, including apoptosis. The mRNA expression revealed that pRVA activates the interferon-mediated pathway while regulating NF-κB signaling, allowing prolonged detection of viral RNA and oncolysis. Induction of immune checkpoints upon pRVA infection enables the infected cell to evade immune recognition, thereby promoting delayed viral RNA clearance while enhancing oncolysis. The pRVA infection selectively modulates toll-like receptor (TLRs), viral RNA-sensing endosomal TLRs, suggesting coordinated innate immune sensing and immune checkpoint regulation. Inflammatory cytokines, including IL-6sR, IP-10, MIP-1γ, and RANTES, were inhibited after infection, suggesting a unique immune evasion by the rotavirus. This immune modulation may facilitate sustained viral RNA presence and support the potential utility of pRVA as an oncolytic virus.