Targeting macrophage-driven NK cell immunosuppression to improve cancer immunotherapy

Natural killer (NK) cells are critical effectors of antitumor immunity, however their cytotoxic function is frequently impaired within the tumor microenvironment (TME). Tumor-associated macrophages (TAMs), the most abundant immune stromal population in solid tumors, play a central role in shaping NK cell responses through a broad range of mechanisms, including receptor-ligand interactions, immunosuppressive cytokine signaling, metabolic reprogramming, and engagement of immune checkpoint pathways. Here, we review current insights into the bidirectional crosstalk between TAMs and NK cells and discuss therapeutic strategies aimed at restoring NK cell activity by targeting TAMs. These include macrophage depletion and reprogramming approaches, modulation of metabolic and transcriptional pathways, and interventions targeting cytokine networks and immune checkpoints. We further examine emerging strategies that reshape the TME to enhance NK-macrophage cooperation, such as induction of inflammatory cell death, modulation of innate immune signaling pathways, and the development of synthetic NK cell engagers. In addition, we highlight the impact of macrophage ontogeny, tissue residency, and spatial organization on NK cell function, emphasizing how distinct microanatomical niches within the TME regulate immune cell interactions and influence therapeutic responses. Finally, we summarize translational advances and ongoing clinical efforts aimed at integrating TAM-targeted therapies with NK cell-based approaches. Collectively, these findings provide a conceptual and mechanistic framework for the rational design of combination immunotherapies that leverage macrophage-NK cell interactions to enhance innate immune responses and improve cancer treatment outcomes.