LKB1是肺癌中最常见突变基因之一，临床研究发现该突变肺癌患者接受抗PD-1免疫治疗效果不佳，但具体分子机制仍未完全阐明。我们前期通过TCGA、CCLE等大数据库及细胞学实验发现：LKB1突变肺癌NKG2D配体（NKG2DL）表达显著减少，而NKG2DL是激发NK细胞固有免疫效应的关键节点。已知研究发现：LKB1激活下游盐诱导激酶（SIK）阻断组蛋白乙酰化酶（HDAC）活性，HDAC抑制剂诱导肿瘤细胞NKG2DL表达，据此，我们推测：肺癌中LKB1缺陷去抑制HDAC活性阻断NKG2DL诱导表达，介导固有免疫抵抗，导致免疫治疗原发耐药。本研究拟通过细胞学实验、小鼠肺癌模型及临床标本检测等方法，阐述LKB1缺陷通过SIK-HDAC通路调控NKG2DL诱导表达介导固有免疫抵抗的分子机制，探讨恢复NKG2DL表达联合抗PD-1克服LKB1缺陷肺癌耐药效果，为进一步开展前瞻性临床试验提供科学依据。

LKB1 is one of the most common mutant genes in lung cancer. Clinical studies have found that anti-PD-1 immunotherapy is not effective in patients with this mutant lung cancer, but the specific molecular mechanism is still not fully elucidated. In our previous studies, we found that the expression of NKG2D ligand (NKG2DL) in LKB1 mutant lung cancer was significantly reduced, and NKG2DL was the key node to stimulate the innate immune response of NK cells. It has been found that LKB1 activates downstream salt-induced kinase (SIK) to block histone acetylase (HDAC) activity and HDAC inhibitors to induce NKG2DL expression in cancer cells. Therefore, we speculate that LKB1 deficiency in lung cancer can inhibit HDAC activity to block NKG2DL induced expression and mediate innate immune resistance, leading to primary resistance to immunotherapy. The purpose of this study is to elucidate the molecular mechanism of LKB1 defect regulating NKG2DL-induced expression and intrinsic immune resistance through SIK-HDAC pathway through cytological experiments, lung cancer model in mice and clinical specimen detection, and to explore the effect of restoring NKG2DL expression combined with anti-PD-1 in overcoming LKB1-deficient lung cancer resistance, so as to provide scientific basis for further prospective clinical trials.