Mechanisms and strategies for reversing NK cell exhaustion in tumor immunotherapy

Natural Killer (NK) cells play a crucial role in the body's innate immune system, distinguished by their ability to target a wide array of tumors through diverse killing strategies. Following the intense focus on T cells, NK cells have emerged as a key player in immunotherapy. Recent advancements in NK cell-based cancer treatments, including adoptive cell therapy, immune checkpoint inhibition, recombinant cytokine therapies, and nanomedicines, have demonstrated promising outcomes both in vitro and in vivo. As research into NK cell-based therapies intensifies, evidence is mounting that NK cells undergo phenotypic changes, acquiring characteristics of exhaustion. Key features comprise reduced proliferative capacity, diminished cytokine production, altered receptor expression, as well as compromised lymph node homing and Tumor Microenvironment (TME) persistence. NK cell exhaustion not only reduces NK cell efficacy and number in solid tumor therapies, but it also plays a crucial role in treatment resistance and tumor cell evasion. Understanding the mechanisms behind NK cell exhaustion and developing strategies to counteract it within the suppressive TME are of paramount importance. In this review, we delineate the maturation and development of NK cells, emphasize the phenotypic characteristics and underlying mechanisms of NK cell exhaustion, systematically review the methods to mitigate NK cell exhaustion, and thoroughly discuss the current limitations of NK cell immunotherapy. Ultimately, we aim to provide potential solutions and future directions for enhancing NK cell-based cancer treatments.