Novel therapeutic strategies for ccRCC through integration of systemic drug combinations and oncolytic adenovirus immunotherapy.

INTRODUCTION: Clear cell renal cell carcinoma (ccRCC) remains a significant therapeutic challenge due to its biological heterogeneity, variable clinical behavior, and limited efficacy of single-agent systemic therapies. Combination strategies targeting multiple tumor-promoting pathways may improve therapeutic outcomes. METHODS: We evaluated combination treatment strategies integrating targeted systemic drugs with oncolytic adenovirus therapy using representative patient-derived cancer cell (PDC) models. Anti-tumor efficacy and immune-mediated cytotoxicity were assessed to investigate treatment responses across different patient-derived models. RESULTS: Combination treatment enhanced anti-tumor activity compared with either monotherapy alone and promoted immune-mediated cytotoxicity involving CD8+ T cells and natural killer (NK) cells. Treatment responses varied across the three PDC models, reflecting interpatient heterogeneity and suggesting potential value for biomarker-guided patient stratification. DISCUSSION: These findings demonstrate the potential of combining targeted therapy with oncolytic virotherapy to overcome current therapeutic limitations in ccRCC. Moreover, the use of advanced three-dimensional human-relevant PDC models provides a scalable platform for evaluating combination therapies, supporting personalized treatment strategies, and facilitating the development of therapeutic approaches applicable to ccRCC and other cancer types.