Engineered innate immune cells in combination cancer therapy: mechanism, challenges, and future

Cancer immunotherapy has transformed oncology, yet most advances have focused on T-cell–based modalities, which encounter major limitations in solid tumors due to poor infiltration and strong immunosuppression. Engineered innate immune cells—including natural killer (NK) cells, macrophages, and dendritic cells, have emerged as promising alternatives with intrinsic capabilities for tumor recognition and cytotoxicity. This narrative review synthesizes current preclinical and clinical evidence on genetically and functionally engineered innate immune cells used in combination cancer therapies. Peer-reviewed studies were examined to characterize engineering strategies, antitumor mechanisms, and synergy with conventional and immunotherapeutic modalities. Engineered innate immune cells demonstrate enhanced tumor-homing potential, improved cytotoxicity, and the ability to reshape the tumor microenvironment. Their combination with chemotherapy, radiotherapy, immune checkpoint inhibitors, oncolytic viruses, or adoptive T-cell therapies shows synergistic antitumor activity across various solid and hematologic malignancies. Key translational challenges include manufacturing scalability, persistence, safety concerns, and variability in patient responses. Rational combination regimens incorporating engineered innate immune cells offer a powerful strategy to overcome resistance in solid tumors and may significantly improve clinical outcomes. Future innovations, such as synthetic biology tools, logic-gated receptors, and nanomedicine-based delivery systems, are expected to accelerate the clinical integration of these therapies.