Beyond KIR and NKG2A blockade: reprogramming NK-cell immunity in solid tumors

Natural killer (NK) cells are uniquely equipped to eliminate transformed cells without prior antigen sensitization, yet their therapeutic potential in solid tumors remains only partially realized. At the center of this paradox lies a complex network of inhibitory pathways, dominated by killer cell immunoglobulin-like receptors (KIRs) and the CD94/NKG2A axis, which continuously calibrate NK-cell self-tolerance and effector competence. Tumors exploit these regulatory circuits through dynamic remodeling of HLA-I expression: while loss of classical HLA-I impairs CD8⁺ T-cell recognition, preservation or upregulation of non-classical HLA, particularly HLA-E, sustains inhibitory signaling and promotes immune escape. These mechanisms are further amplified by the tumor microenvironment (TME), where stromal barriers, hypoxia, metabolic stress, and immunosuppressive networks collectively restrict NK-cell infiltration, persistence, and cytotoxicity. Such multilayered suppression helps explain why therapeutic blockade of KIR or NKG2A alone has yielded only modest clinical benefit in most solid tumors, despite compelling biological rationale. Emerging evidence suggests that the KIR- and CD94/NKG2-centered network should be viewed not only as a therapeutic target but also as a framework for the next-generation of NK-cell-based immunotherapies. Future strategies will likely combine checkpoint modulation with donor- and patient-tailored NK-cell selection, engineered NK-cell products with enhanced metabolic resilience and reduced checkpoint sensitivity, and interventions aimed at remodeling the tumor niche to restore trafficking, persistence, and functional fitness. In this mini-review, we discuss how KIR- and CD94/NKG2-mediated signaling is shaped by the TME and examine emerging combinatorial and personalized approaches designed to unlock the full therapeutic potential of NK cells in solid tumors.