Natural killer (NK) cells are effector lymphocytes with pivotal roles in the resistance against various tumors; dysfunction of NK cells often results in advanced tumor progression. Tumors develop in three stages comprising initiation, promotion, and progression, but little is known about the interrelationships between NK cells and tumor cells at different stages of tumor development. Here, we demonstrated that NK cells prevented tumor initiation potently but did not prevent tumor promotion or tumor progression in Kras-driven lung cancer. Moreover, loss of the antitumor effect in NK cells was closely associated with their dysfunctional state during tumor promotion and progression. Mechanistically, aberrant fructose-1,6-bisphosphatase (FBP1) expression in NK cells elicited their dysfunction by inhibiting glycolysis and impairing viability. Thus, our results show dynamic alterations of NK cells during tumor development and uncover a novel mechanism involved in NK cell dysfunction, suggesting potential directions for NK cell-based cancer immunotherapy involving FBP1 targeting.

The lungs, a special site that is frequently challenged by tumors, pathogens and other environmental insults, are populated by large numbers of innate immune cells. Among these, natural killer (NK) cells are gaining increasing attention. Recent studies have revealed that NK cells are heterogeneous populations consisting of distinct subpopulations with diverse characteristics, some of which are determined by their local tissue microenvironment. Most current information about NK cells comes from studies of NK cells from the peripheral blood of humans and NK cells from the spleen and bone marrow of mice. However, the functions and phenotypes of lung NK cells differ from those of NK cells in other tissues. Here, we provide an overview of human and mouse lung NK cells in the context of homeostasis, pathogenic infections, asthma, chronic obstructive pulmonary disease (COPD) and lung cancer, mainly focusing on their phenotype, function, frequency, and their potential role in pathogenesis or immune defense. A comprehensive understanding of the biology of NK cells in the lungs will aid the development of NK cell-based immunotherapies for the treatment of lung diseases.

Natural killer (NK) cells are reported to have immunological memory, with CD49a+ liver-resident NK cells shown to confer hapten-specific memory responses, but how this memory is induced or maintained is unclear. Here we show that memory type I innate lymphoid cells (ILC1s), which express IL-7Rα, are generated in the lymph nodes (LNs) and require IL-7R signaling to maintain their longevity in the liver. Hapten sensitization initiates CXCR3-dependent recruitment of IL-7Rα+ ILC1s into skin-draining LNs, where they are primed and acquire hapten-specific memory potential. Memory IL-7Rα+ ILC1s then exit draining LNs and are preferentially recruited, via CXCR6, to reside in the liver. Moreover, long-term blockade of IL-7R signaling significantly reduces ILC1-mediated memory responses. Thus, our results identify a memory IL-7Rα+ ILC1 population and reveal a LN-liver axis that is essential for ILC1 memory generation and long-term maintenance.

Gemcitabine has been used as first-line chemotherapy against lung cancer, but many patients experience cancer recurrence. Activation of anti-tumor immunity in vivo has become an important way to prevent recurrence. Anti-tumor immune responses are often dependent upon the immunogenicity of tumors. In our study, we observed that low-dose gemcitabine treatment enhanced the immunogenicity of lung cancer by increasing the exposure of calreticulin, high mobility group box 1, and upregulating expression of NKG2D ligands. Further studies demonstrated that low-dose gemcitabine treatment increased interferon-γ expression and NK-cell activation in mice. Low-dose gemcitabine treatment was sufficient for inhibiting tumor growth with few side effects in vivo. These data suggest that low-dose gemcitabine-induced immunochemotherapy activated antitumor immunity in immunocompetent patients.

Natural killer (NK) cells are the host's first line of defense against tumors and viral infections without prior sensitization. It is increasingly accepted that NK cells belong to the innate lymphoid cell (ILC) family. Other ILCs, comprising ILC1s, ILC2s, ILC3s and lymphoid tissue inducer (LTi) cells, are largely non-cytotoxic, tissue-resident cells, which function to protect local microenvironments against tissue insults and maintain homeostasis. Recently, evidence has accumulated that metabolism supports many aspects of the biology of NK cells and other ILCs, and that metabolic reprogramming regulates their development and function. Here, we outline the current understanding of ILC metabolism, and describe how metabolic processes are affected, and how metabolic defects are coupled to dysfunction of ILCs, in disease settings. Furthermore, we summarize the current and potential directions for immunotherapy involving targeting of ILC metabolism. Finally, we discuss the open questions in the rapidly expanding field of ILC metabolism.