NK cell adaptation in the tumor microenvironment: Insights for NK cell-based immunotherapy

Natural killer (NK) cells serve as critical first responders within the immune system, orchestrating antitumor responses by directly eliminating malignant cells and modulating broader immune functions. Their capacity to recognize stressed targets without MHC-restricted neoantigen presentation, together with a favorable safety profile, underpins growing enthusiasm for NK cell‑based therapeutics. Nonetheless, the clinical efficacy of NK-cell-based therapies in solid tumor has been hindered by tumor microenvironment (TME)-driven immunosuppression, metabolic competition, and cell-intrinsic exhaustion mechanisms. In this review, we outline the journey from the discovery of NK cells to their role as a breakthrough target in cancer immunotherapy. We then provide a comprehensive framework of NK cell biology, from homeostatic regulation to TME-driven epigenetic, transcriptional, and metabolic adaptations. Notably, we discuss recent investigations into NK cell subset heterogeneity and their interactions with tumor cells, immune cells and the gut microbiome. Finally, we critically evaluated clinical progress while highlighting the imperative for rationally designed, mechanism-based combinations that address tumor escape pathways. The review concludes with a forward-looking perspective on engineering solutions to unlock the full therapeutic potential of NK cells across solid tumors and hematologic malignancies.