Collectively, our findings demonstrate that oAd armed with multiple immune-stimulatory and ECM-degrading therapeutic genes can outperform those observed using oAd expressing GM-CSF as a single therapeutic gene and that it could synergize with 9-ING-41 to induce robust degradation of tumor ECM and tumor-specific immune response and prevent immune cell exhaustion, ultimately enabling effective control of primary and metastatic bladder tumor growth. The gene discussed is CSF2; the disease is urinary bladder neoplasm.