Natural killer (NK) cells play a crucial role in the immune defense against cancer, with their presence in solid tumors often linked to improved patient outcomes in various cancers. However, NK cells encounter numerous challenges in the solid tumor microenvironment (TME). These challenges include downregulation of activating receptors on NK cells, inducing NK cell plasticity towards a stressed, non-cytotoxic tissue-resident phenotype, secretion of inhibitory molecules and metabolites, expression of inhibitory receptors by tumor cells, and creating a hypoxic, immunosuppressive environment. Additionally, the TME imposes metabolic shifts in NK cells and physical barriers that prevent NK cell infiltration and function, even affecting NK cells beyond the immediate tumor vicinity. Despite these suppressive conditions, intratumoral NK cells can retain cytotoxic capacity under certain conditions, suggesting therapeutic potential if immunosuppressive signals can be counteracted. A comprehensive understanding of these suppressive mechanisms and metabolic reprogramming is essential for developing effective NK cell-based therapies for solid tumors. Genetic engineering strategies aim to improve NK cell persistence, tumor infiltration, and resistance to immunosuppression. Future strategies may also include targeting tumor metabolism, leveraging NK cell-derived extracellular vesicles, and using NK cells to target both cancerous and cancer-associated non-tumor cells, further expanding the therapeutic potential of NK cell-based interventions. These advancements pave the way for groundbreaking cancer immunotherapies leveraging NK cells.