Natural killer (NK) cells are key effectors of the innate immune system, playing a central role in recognizing and eliminating malignant cells. This chapter focuses on the lytic immunological synapse (IS) formed by NK cells, which is essential for their cytotoxic function against tumors. We review recent advances in understanding the NK cell IS, emphasizing its structural organization, molecular composition, and functional dynamics within the tumor microenvironment (TME). Emerging evidence highlights how various TME-associated factors, including cellular interactions and physical constraints, modulate IS formation and function, ultimately influencing NK cell-mediated tumor clearance. Furthermore, we explore tumor immune evasion strategies that impair IS integrity, such as disrupted synapse formation, suppression of activating signals, and reinforcement of inhibitory pathways, which collectively enable tumor cells to escape NK cell cytotoxicity and promote disease progression. By integrating current research, this chapter provides a comprehensive overview of the complex interplay between NK cells and the TME through the lens of the IS. A deeper understanding of these interactions is crucial for developing novel therapeutic approaches to enhance NK cell synapse formation and function, thereby improving their anti-tumor efficacy. Our discussion bridges basic immunological research with clinical applications, highlighting potential interventions to potentiate NK cell activity against cancer.