自然杀伤(NK)细胞是先天性免疫细胞，是机体对抗感染和肿瘤发生的第一道防线。我们近期报导了XBP1s作为IL-15-AKT信号下游重要的转录因子，可调控原代人NK细胞杀伤活性和生存。然而，XBP1s下游具体的分子调节机制尚不清楚。预实验显示，在NK细胞Xbp1基因条件敲除小鼠外周血及多器官中NK细胞数量显著下调，且促进荷瘤小鼠的肿瘤进展；高表达XBP1s可促进AKT和NF-kappaB信号的活化，提示了XBP1s调节NK细胞功能与生存的潜在机制。我们设想，XBP1s通过AKT和IKK激酶复合体信号，调节下游NF-kappaB的转录活性，从而实现对NK细胞免疫功能及生存的影响。探索XBP1s调控NK细胞的分子机制，确定其作为靶点的生物学功能，确立表达活化型XBP1s的靶向方法，为NK或CAR-NK细胞抗肿瘤治疗中所面临的肿瘤微环境免疫抑制问题提供全新的应对策略。

We have demonstrated that XBP1s, a downstream transcriptional factor of IL-15, regulated NK cell cytotoxicity, functional genes expression and survival. Our preliminary data showed that deficiency of XBP1 gene induced the reduction of NK cell quantities in various organs in murine NK cells and promotes tumor progression. NK or CAR-NK cells cannot persist long after being infused into patients, and NK cell exhaustion and tumor cell resistance to NK cell cytotoxicity caused by an inhospitable tumor microenvironment. These results suggest that XBP1s may serve as a promising molecule target for NK cell-based therapy by enhancing NK cell survival and anti-tumor activity in the tumor microenvironment. However, the regulatory mechanisms of XBP1s-induced NK cell effector functions and survival are still unclear. Further investigation will be performed to determine the underlying mechanisms of the NK cell effector function and survival by the regulation of XBP1s-AKT/IkappaB kinase(IKK) complex-NF-kappaB axis. In addition, we will explore the possibilities that XBP1s can be a potential molecule target to enhance the anti-tumor efficacy of NK or CAR-NK cell-based therapy. Our study will provide a novel therapeutic strategy for dealing with ongoing low efficiency problems on certain anti-tumor immunotherapies caused by short-lifespan of NK cells and tumor cell resistance to NK cell-mediated cytotoxicity.