Unleashing NK cells for cancer immunotherapy in lung cancer: biologic challenges and clinical advances.

Natural killer (NK) cells are a crucial part of the innate immune system and serve as an important effector for killing tumor cells through direct cytolytic activity or immunomodulatory signaling to T cells and antigen presenting cells. NK cells are correlated with increased tumor control and better overall patient survival across various types of cancers including non-small cell lung cancer (NSCLC). Despite their promising potential for anti-tumor killing, NK cell function is often diminished within the tumor microenvironment. There are many factors that lead to decreased tumor-infiltrating NK cell killing, including immunoinhibitory factors from tumor cells and resident tissues, acquired immune tolerance, NK cell exhaustion, and the hypoxic state of the tumor microenvironment. Unleashing NK cell activity therefore has high potential to create a new class of immunotherapy that could combat both primary and acquired resistance to current checkpoint inhibitors. In this review we discuss mechanistic details of NK cell tumor killing, NK cell immunosuppression, and gaps in knowledge regarding highly complex microenvironment-specific effects on NK cell function. We also discuss the promise and limitations of emerging NK-cell based therapeutic strategies.