Arboviruses in Cancer therapy: pros and cons.

Arboviruses, arthropod-borne RNA viruses, are increasingly being recognized not only as causative agents of infectious diseases but also as promising tools in cancer therapy. Recent studies have demonstrated that certain arboviruses possess inherent oncolytic properties and can stimulate potent antitumor immune responses. This review critically examines the therapeutic potential of arboviruses in oncology alongside the key biosafety and translational challenges they present. Several members of the Flaviviridae, Reoviridae, Togaviridae, and Bunyaviridae families, such as Zika virus (ZIKV), Dengue virus (DENV), Yellow Fever virus (YFV), West Nile virus (WNV), Reovirus, Alphavirus, and Rift Valley Fever virus (RVFV), have shown tumor-selective cytotoxicity and strong immunogenicity. ZIKV targets glioblastoma stem-like cells via CD24/SOX2-integrin αvβ5 signaling, while DENV enhances cytotoxic T lymphocyte activity through TRAIL and cytokine induction. These viruses can reprogram the tumor microenvironment by promoting innate and adaptive immune activation, making them attractive candidates for combination with immune checkpoint inhibitors. Despite these advantages, major concerns remain, including viral neurotropism, off-target effects, environmental transmission via vectors, and the impact of pre-existing immunity in endemic regions. In immunocompromised patients, even attenuated strains may pose safety risks. To unlock the full clinical potential of arboviruses in cancer treatment, future strategies must focus on improving tumor specificity through genetic engineering and mitigating biosafety risks. Arbovirus-based virotherapy offers a novel immunotherapeutic avenue capable of turning immunologically “cold” tumors into “hot” ones, thus enhancing cancer immunotherapy outcomes.