Abstract / Summary
Prostate cancer presents major treatment challenges after progression to metastatic castration-resistant prostate cancer (mCRPC). Tumor heterogeneity, lineage plasticity, bone metastases, and an immunosuppressive tumor microenvironment can weaken treatment responses and support disease persistence. Natural killer (NK) cells are innate immune effectors that recognize susceptible tumor cells, mediate antibody-dependent cellular cytotoxicity (ADCC), and release immunomodulatory cytokines. These functions have led to growing interest in NK cell-based therapies for prostate cancer. This review explores impaired immune function, differences among tumor cell populations, current treatment limitations, and recent progress in NK therapy development. Prostate-specific studies have investigated prostate-specific membrane antigen (PSMA)-directed chimeric antigen receptor (CAR)-NK cells, a PSMA × CD16 × interleukin-15 trispecific killer engager, antibody-redirected peripheral blood NK cells, PARP inhibitor combinations, and NK-mediated killing of stem-enriched PC3 cells. Tumor profiling has also associated a higher inferred NK cell fraction with favorable outcomes, although this association does not establish a treatment effect. Studies of supercharged NK cells in other cancers suggest potential for targeting diverse tumor populations and promoting tumor differentiation, providing a rationale for prostate-specific testing. Early clinical investigation includes a first-in-human conference report, while durable efficacy and survival benefits remain unproven. Future efforts should address tumor and antigen diversity, activity within bone lesions, normal-tissue safety, manufacturing consistency, and patient access, while evaluating rational combinations with established treatments.