肺癌是全世界癌症死亡的主要原因。 KRAS 癌基因导致至少四分之一的肺腺癌（肺癌的主要亚型）。经过四十年的深入研究，KRAS 癌蛋白的选择性抑制剂终于进入临床。然而，由于耐药性的迅速出现，它们对总体生存的影响有限，这可能是这些肿瘤的高瘤内异质性特征的结果。在这项研究中，我们试图确定在肿瘤发展的最早阶段 KRAS 癌蛋白表达导致的功能改变。无论是否存在其他同时发生的突变，这种功能变化都可能在肿瘤进展的整个过程中持续存在。对表达 Kras 常驻癌基因的小鼠肺泡 2 型细胞的单细胞 RNA 测序分析显示，I 型干扰素途径受损，这是在整个肿瘤进展过程中持续存在的特征。这种改变也存在于含有 p53 或 LKB1 肿瘤抑制因子额外突变的晚期小鼠和人类肿瘤中。通过 IFN-β 或干扰素基因组成型活性刺激物 (STING) 表达恢复 I 型干扰素 (IFN) 信号对肿瘤微环境产生深远影响，将肿瘤从免疫学“冷”肿瘤转变为免疫学“热”肿瘤。因此，无论 p53 或 LKB1 是否同时发生突变，I 型 IFN 通路的增强都使 KRAS 突变肺肿瘤易于接受免疫治疗。

Lung cancer is the leading cause of cancer mortality worldwide. KRAS oncogenes are responsible for at least a quarter of lung adenocarcinomas, the main subtype of lung cancer. After four decades of intense research, selective inhibitors of KRAS oncoproteins are finally reaching the clinic. Yet, their effect on overall survival is limited due to the rapid appearance of drug resistance, a likely consequence of the high intratumoral heterogeneity characteristic of these tumors. In this study, we have attempted to identify those functional alterations that result from KRAS oncoprotein expression during the earliest stages of tumor development. Such functional changes are likely to be maintained during the entire process of tumor progression regardless of additional co-occurring mutations. Single-cell RNA sequencing analysis of murine alveolar type 2 cells expressing a resident Kras oncogene revealed impairment of the type I interferon pathway, a feature maintained throughout tumor progression. This alteration was also present in advanced murine and human tumors harboring additional mutations in the p53 or LKB1 tumor suppressors. Restoration of type I interferon (IFN) signaling by IFN-β or constitutive active stimulator of interferon genes (STING) expression had a profound influence on the tumor microenvironment, switching them from immunologically "cold" to immunologically "hot" tumors. Therefore, enhancement of the type I IFN pathway predisposes KRAS mutant lung tumors to immunotherapy treatments, regardless of co-occurring mutations in p53 or LKB1.