Tumor microenvironment-driven natural killer cell diversity: mechanisms and therapeutic opportunities

Natural killer (NK) cells are key effector cells involved in tumor immune surveillance, yet their function within the tumor microenvironment (TME) exhibits considerable complexity and plasticity that cannot be adequately explained by the classical CD56/CD16 dichotomy. This functional diversity arises from the phenotypic adaptability and dynamic differentiation of distinct NK cell subsets shaped by the TME. In this review, we systematically examine the defining characteristics and functional roles of recently identified NK cell subsets in the TME; elucidate the molecular mechanisms governing their regulation; and highlight the functional transitions and cooperative interactions among these subsets. Moreover, building on current evidence, we summarize emerging immunotherapeutic approaches targeting specific NK cell subsets. Together, these perspectives offer new insights and strategic directions for deciphering the multifaceted roles of NK cells in antitumor immunity and advancing the development of subset-targeted therapies.