目前，肺癌的治疗选择最多，其益处基于多项大规模测序研究、转化研究和新药开发，这促进了我们对肺癌分子病理学的理解。根据驾驶员的变化，揭示了不同的特征，例如种族流行率、中位年龄和变化模式的差异。因此，除了传统的放化疗之外，分子靶向治疗和免疫检查点抑制剂（ICI）治疗也成为主要的治疗选择。有趣的是，临床结果表明，最近建立的疗法针对不同的肺癌比例，特别是 EGFR/ALK 和 PD-1/PD-L1 阳性亚群之间，例如激酶抑制剂针对驱动突变阳性肿瘤，而驱动突变阴性肿瘤对 ICI 治疗有反应。这些与治疗效果相关的差异可能可以通过肺癌的分子发病机制来解释。成瘾驱动突变具有强大的转化性能，可促进肿瘤形成，从而导致肿瘤突变负担低、免疫监视减少以及随后对 ICI 的不良反应。相反，经常接触烟草烟雾会反复损伤近端气道上皮，导致累积的基因改变。在后一种途径中，由于改变和针对新抗原的免疫排斥而导致的过度生长最初得到平衡。然而，某些克隆可能会产生肿瘤，这些克隆会超越免疫排斥，并且生长速度会超过其他克隆。因此，这种癌症类型对免疫检查点治疗有反应。这些致病性差异可以通过两室模型得到很好的解释，该模型侧重于终末呼吸单位和空气传导系统之间不同细胞成分的解剖学和功能组成。© 2023 作者。组织病理学由约翰·威利出版

Currently, lung cancer is treated by the highest number of therapeutic options and the benefits are based on multiple large-scale sequencing studies, translational research and new drug development, which has promoted our understanding of the molecular pathology of lung cancer. According to the driver alterations, different characteristics have been revealed, such as differences in ethnic prevalence, median age and alteration patterns. Consequently, beyond traditional chemoradiotherapy, molecular-targeted therapy and treatment with immune check-point inhibitors (ICI) also became available major therapeutic options. Interestingly, clinical results suggest that the recently established therapies target distinct lung cancer proportions, particularly between the EGFR/ALK and PD-1/PD-L1-positive subsets, e.g. the kinase inhibitors target driver mutation-positive tumours, whereas driver mutation-negative tumours respond to ICI treatment. These therapeutic efficacy-related differences might be explained by the molecular pathogenesis of lung cancer. Addictive driver mutations promote tumour formation with powerful transformation performance, resulting in a low tumour mutation burden, reduced immune surveillance, and subsequent poor response to ICIs. In contrast, regular tobacco smoke exposure repeatedly injures the proximal airway epithelium, leading to accumulated genetic alterations. In the latter pathway, overgrowth due to alteration and immunological exclusion against neoantigens is initially balanced. However, tumours could be generated from certain clones that outcompete immunological exclusion and outgrow the others. Consequently, this cancer type responds to immune check-point treatment. These pathogenic differences are explained well by the two-compartment model, focusing upon the anatomical and functional composition of distinct cellular components between the terminal respiratory unit and the air-conducting system.© 2023 The Authors. Histopathology published by John Wiley & Sons Ltd.