Natural killer and CAR-NK cell therapies in urological cancers: Progress, mechanistic lessons from CAR-T, and future directions.

This review aims to synthesize the current progress, challenges, and future directions of Natural Killer (NK) and Chimeric Antigen Receptor-NK (CAR-NK) cell therapies for urological cancers, including renal cell carcinoma, bladder cancer, and prostate cancer. We detail the unique biology of NK cells, such as 'missing-self' recognition and intrinsic antibody-dependent cellular cytotoxicity (ADCC), which offer potential safety and efficacy advantages over CAR-T cells, including a lower risk of severe cytokine release syndrome and graft-versus-host disease. The analysis covers conventional NK-based strategies, the engineering and 'armouring' of CAR-NK platforms to overcome the immunosuppressive tumour microenvironment, and preclinical and early clinical advances with target antigens like CAIX, CD70, PSMA, and nectin-4 across different urological malignancies. We conclude that while CAR-NK therapy represents a promising 'off-the-shelf' modality for these cancers, its success in solid tumours hinges on next-generation designs that solve critical challenges of in vivo persistence, efficient tumour homing, and resistance to local metabolic and immunosuppressive pressures.