A systematic review of natural killer cell clinical trials: Trends, Innovations and the Rise of CAR NK and iPSC NK Immunotherapy

The global development of natural killer (NK) cell–based immunotherapy has undergone transformative growth over the past two decades. This systematic review analyzes 326 registered interventional clinical trials updated to April 2025 from ClinicalTrials.gov, ICTRP, and Chinese clinical trial registries, covering indications, clinical phases, cell sources, geographical distribution, allogeneic/autologous sourcing, dosing, administration routes, and manufacturing platforms. We highlight paradigm shifts toward off the shelf chimeric antigen receptor NK (CAR NK) and induced pluripotent stem cell–derived NK (iPSC NK) as next generation platforms with validated efficacy in hematologic malignancies, solid tumors, viral infections, and emerging autoimmune diseases. Key advances include standardized GMP manufacturing, enhanced in vivo persistence, blood–brain barrier penetration for glioblastoma (GBM), and favorable safety profiles with minimal cytokine release syndrome (CRS), neurotoxicity (ICANS), or graft versus host disease (GvHD). This review integrates updated trial data, mechanistic innovations, tissue resident NK (trNK) biology, and breakthrough clinical outcomes to map global trends and forecast the future of NK cell immunotherapy.