HDAC6 orchestrates NK cell maturation and antitumor immunity

Natural killer (NK) cells act as the host's first line of immunosurveillance, and their maturation and effector functions are finely regulated by multiple factors. Although histone deacetylase (HDAC) inhibition has been reported to impair NK cell viability and/or antitumor effects, the specific HDAC member involved and the underlying mechanisms remain unclear.

We analyzed the expression of HDAC family members during NK cell activation and in tumor-infiltrating NK cells. Genetic approaches, including Hdac6 knockout, knockdown, and overexpression, were used to evaluate its role in NK cell proliferation, maturation, and effector function. Mechanistic studies examined protein acetylation status, chaperone activity, and IL-15-STAT5 signaling. Functional relevance was assessed using NK cell adoptive transfer models and interleukin (IL)-15 combination treatment in tumor settings.

HDAC6 was the most significantly upregulated HDAC member on NK cell activation, whereas its expression was reduced in tumor-infiltrating NK cells and correlated with poor patient survival. Hdac6 deficiency markedly impaired NK cell proliferation, maturation, and effector functions, while Hdac6 overexpression showed a promoting effect. Mechanistically, loss of Hdac6 led to the hyperacetylation of HSP90, which in turn destroyed its chaperone activity for phosphorylated STAT5 and blocked the transduction of the IL-15 signaling pathway indispensable for NK cell maturation and effector function. Translationally, HDAC6 overexpression not only obviously improved tumor suppression of transferred NK cells, but also synergized with IL-15 treatment to further boost NK cell antitumor efficacy.

HDAC6 was identified as a critical regulator of NK cell biology through strengthening the IL-15/STAT5 pathway and may serve as a potential target for improving NK cell function.