Therapeutic reprogramming of natural killer cells for solid tumors: expanding frontiers into rare and ultra-rare malignancies

Rare and ultra-rare solid tumors collectively account for approximately one-quarter of all cancer diagnoses yet remain associated with poor clinical outcomes. Delayed diagnosis, limited biological characterization, few therapeutic options, and the logistical challenges of conducting adequately powered clinical trials underscore the potential for adaptable cellular immunotherapies that can be applied across diverse tumor histologies. Natural killer (NK) cells have emerged as a promising platform for adoptive cell therapy because of their ability to recognize and eliminate malignant cells independently of major histocompatibility complex restriction, their favorable safety profile, and their suitability for standardized allogeneic, off-the-shelf manufacturing. This review examines the progression of NK cell-based therapies from their biological and therapeutic foundations in solid tumors to their emerging application in rare and ultra-rare malignancies. Recent advances in NK cell engineering are enabling multifunctional cell products designed to enhance tumor recognition, trafficking, persistence, and resistance to the immunosuppressive tumor microenvironment. We also review emerging clinical evidence demonstrating the feasibility and safety of these approaches while highlighting the major biological and translational barriers that continue to limit durable responses. Building on these advances, attention is given to the unique challenges of rare and ultra-rare cancers, where small patient populations, tumor heterogeneity, limited therapeutic targets, and logistical constraints pose unique challenges to conventional drug and cellular therapy development. Finally, we discuss how scalable off-the-shelf manufacturing, rational combination strategies, innovative clinical trial designs, and next-generation technologies, including multiplex gene editing, armored NK cells, and in vivo engineering, may facilitate this translation. Collectively, progress in NK cell therapy across solid tumors provides a framework for extending increasingly adaptable and scalable immunotherapeutic platforms to rare and ultra-rare malignancies, with the potential to expand treatment opportunities for patient populations that have historically had limited therapeutic options.