Natural Killer Cell Immunotherapy in Solid Tumors: Microenvironmental Obstacles and Translational 3D Models

Natural killer (NK) cells represent a promising tool for cancer immunotherapy; however, their efficacy against solid tumors is severely limited by the hostile tumor microenvironment (TME). This review provides a comprehensive overview of the physical, molecular, and metabolic barriers that drive NK cell dysfunction and immune evasion, emphasizing the physical challenge posed by extracellular matrix (ECM) density, which restricts infiltration. Beyond structural barriers, we examine the role of immunosuppressive cytokines (e.g., TGF-β) and immune checkpoint upregulation, both of which directly inhibit NK cell activation. Furthermore, NK cell signaling and cytotoxicity are profoundly affected by metabolic stressors such as hypoxia and acidosis, which act synergistically with the accumulation of immunosuppressive metabolites, including adenosine. These factors impair antitumor activity through multiple mechanisms, particularly the shedding of activating ligands. To investigate these complex interactions, we evaluate the advantages and disadvantages of different three-dimensional (3D) preclinical platforms, including tumor spheroids and Organ-on-Chip technologies, highlighting their distinct characteristics. Rather than advocating for a single technology, we emphasize that each model offers unique advantages for studying specific physical, chemical, and cellular components of the TME. Ultimately, leveraging the capabilities of these advanced 3D platforms is essential for deciphering microenvironmental barriers and unlocking the full therapeutic potential of NK cells against solid tumors.