Cytotoxic effect of bladder cancer oncolytic virus on bladder cancer stem-like cells via pyroptosis pathway

Background: The main treatment plan for bladder cancer is surgery combined with postoperative chemotherapy. Patients often suffer from various adverse reactions after chemotherapy, which reduces the quality of life. Moreover, after chemotherapy, the resistance to chemotherapy drugs of tumor is often increased, and the tumor resistance to chemotherapy drugs is often accompanied by the deterioration of pathological classification, distant metastasis, and the decline of patients’ survival period. Recent studies have found that cancer stem cells play a crucial role in tumor proliferation, invasion, metastasis and drug resistance. Objective: This study would prove oncolytic adenovirus Ad5-E1A-UPII-PSCAE emerges as a potent agent against bladder cancer stem-like cells (CSCs), and triggers reactive oxygen species (ROS) accumulation, culminating in pyroptosis. Methods: This study is based on transcriptome and proteomic analysis, supplemented by in vivo and in vitro experiments for validation. Result: In vitro studies confirmed dose-dependent CSC killing (IC50: 3.6 × 10 9 PFU), while transcriptomic and proteomic analyses highlighted mitochondrial dysfunction and ROS-driven pathways as central mechanisms. In vivo, OV-treated xenografts exhibited significant tumor regression and histopathological necrosis. By exploiting the NO/ROS-pyroptosis axis, Ad5-E1A-UPII-PSCAE overcomes CSC-mediated chemoresistance, offering a dual strategy to eradicate aggressive tumor subpopulations and suppress recurrence. Conclusion: This study results demonstrated that OVs could kill cancer stem-like cells by promoting ROS levels, which induce cell pyroptosis.