Engineering the tumor microenvironment: oncolytic NDV to facilitate CAR-T cell therapy.

Chimeric antigen receptor (CAR)-T cell therapy has achieved significant progress in the treatment of hematologic cancers but continues to face major obstacles in solid tumors, including antigen heterogeneity, limited infiltration, and an immunosuppressive tumor microenvironment (TME). Oncolytic viruses (OVs) have emerged as promising tools to reshape the TME and improve CAR-T cell activity, yet many OVs encounter translational hurdles due to human seroprevalence and safety concerns. Newcastle disease virus (NDV), a naturally tumor-selective avian paramyxovirus, offers unique advantages as a non-integrating, non-pathogenic platform with a longstanding veterinary safety record and minimal pre-existing immunity in humans. NDV mediates direct oncolysis and immunogenic cell death, while simultaneously activating dendritic cells, repolarizing macrophages, and enhancing immune cell recruitment, thereby creating a TME that is more permissive to CAR-T cell therapy. Recent advances have enabled NDV to deliver immunostimulatory payloads locally within tumors, offering synergistic combinations to address CAR-T cell exhaustion and persistence. Looking ahead, further engineering efforts may expand the potential of this combined approach. This review summarizes the biological rationale, preclinical evidence, and translational prospects for integrating NDV with CAR-T cell therapy to improve outcomes in solid tumors.