非小细胞肺癌（NSCLC）的治疗方案由于免疫检查点抑制剂（ICB）产生了卓越的抗癌效果而发生了巨大变化。然而，只有某一子集的患者在接受ICB后才会体验到好处。因此，通过阐明潜在的分子机制并确定新的治疗靶点来增加响应率是至关重要的，以增强非响应者ICB的功效。我们通过多种临床因素将295名接受抗PD-1治疗的NSCLC患者分离，并分析了他们的无进展生存期（PFS）和总生存期（OS）。我们还通过基因集富集分析（GSEA）和突变分析确定了与不同ICB反应的患者中富集的关键信号通路和突变。我们发现，吸烟者对抗PD-1治疗的反应率高于非吸烟者。GSEA结果显示，oxphos和线粒体相关通路在响应者和吸烟者中都显著富集，表明细胞代谢可能在调节对ICB的免疫反应中发挥潜在作用。我们还证明，全反式维甲酸（ATRA）可以显著增强线粒体功能，从而显著增强抗PD-1治疗的功效。我们的临床和生物信息学分析揭示了吸烟引起的代谢转换与免疫治疗反应之间的联系，这可以成为开发有益于从未吸烟的NSCLC患者的新型联合治疗的基础。版权所有 © 2023 Elsevier B.V.。保留所有权利。

The treatment regimen of non-small cell lung cancer (NSCLC) has drastically changed owing to the superior anti-cancer effects generated by the immune-checkpoint blockade (ICB). However, only a subset of patients experience benefit after receiving ICBs. Therefore, it is of paramount importance to increase the response rate by elucidating the underlying molecular mechanisms and identifying novel therapeutic targets to enhance the efficacy of IBCs in non-responders. We analyzed the progression-free survival (PFS) and overall survival (OS) of 295 NSCLC patients who received anti-PD-1 therapy by segregating them with multiple clinical factors including sex, age, race, smoking history, BMI, tumor grade and subtype. We also identified key signaling pathways and mutations that are enriched in patients with distinct responses to ICB by gene set enrichment analysis (GSEA) and mutational analyses. We found that former and current smokers have a higher response rate to anti-PD-1 treatment than non-smokers. GSEA results revealed that oxidative phosphorylation (OXPHOS) and mitochondrial related pathways are significantly enriched in both responders and smokers, suggesting a potential role of cellular metabolism in regulating immune response to ICB. We also demonstrated that all-trans retinoic acid (ATRA) which enhances mitochondrial function significantly enhanced the efficacy of anti-PD-1 treatment in vivo. Our clinical and bioinformatics based analyses revealed a connection between smoking induced metabolic switch and the response to immunotherapy, which can be the basis for developing novel combination therapies that are beneficial to never smoked NSCLC patients.Copyright © 2023 Elsevier B.V. All rights reserved.