NK3 subsets are linked to NK cell exhaustion and immunotherapy responsiveness in tumor

Natural killer (NK) cells constitute the first line of human immune defense. They have attracted extensive research in the field of tumor immunity owing to their potent cytotoxicity, robust cytokine secretion, and immunomodulatory capacity. However, chronic tumor antigen exposure would induce exhaustion in NK cells (NK-ex). This study leverages public single-cell RNA sequencing datasets of NK cells to identify NK-ex subsets and map a transcriptional continuum derived from computational trajectory ordering. Our investigation revealed that NK3 exhibited more exhaustion features compared to other NK subsets in tumor patients. lymphocyte-activation gene 3 (LAG-3) expression is relatively specific enriched in the NK-ex subpopulation. Clinical analyses infer that functionally dominant NK-ex subsets are strongly correlated with responses to immune checkpoint blockade (ICB) therapy, and phenotypic shifts toward exhaustion can be observed post-treatment. This study preliminarily characterizes NK-ex subpopulations and suggests that LAG-3 may participate in regulating the progression of NK cell exhaustion, which could offer potential theoretical references for developing immunotherapeutic strategies targeting NK-ex cells.