Lineage plasticity of the integrated stress response is a hallmark of lung cancer evolution.

Lung adenocarcinoma (LUAD) progresses from a single alveolar type 2 (AT2) cell to a complex, malignant tissue through a multi-step process involving acquisition of high plasticity and stem cell-like traits in a subset of cancer cells. Oncogenic transformation and signals from the tumor microenvironment (TME) activate the integrated stress response (ISR), a key survival mechanism that allows tumor cells to adapt and thrive under stress. Using single-cell transcriptomics, we identified high stemness and plasticity cell clusters in mouse LUAD tumors expressing mutant KRAS and lacking TP53 (KP model), which displayed elevated ISR program expression. Disrupting ISR via the genetic loss of phosphorylated eIF2a (p-eIF2a) or the transcription factor ATF4 hindered LUAD growth and the emergence of high-plasticity, stemness-associated lineages, resulting in the formation of a distinct cell state characterized by mitochondrial dysfunction. Additionally, treatment with ISRIB - a small-molecule ISR inhibitor with low toxicity and cognitive benefits - led to an accumulation of AT2-like LUAD cells, blocking developmental progression and tumorigenesis. In human LUAD, the ISR program is similarly elevated in KRAS-mutant tumors with high plasticity and stemness features and correlates with poor patient outcomes. These findings suggest that ISR is a key driver of LUAD progression and targeting ISR could provide a promising approach to slow LUAD progression and improve lung cancer treatment outcomes.

肺腺癌（LUAD）的发生是一个多步骤过程：由单个II型肺泡上皮细胞（AT2细胞）起始，最终发展为复杂的恶性肿瘤组织，此过程中，部分肿瘤细胞会获得高度可塑性及干细胞样表型。致癌转化与肿瘤微环境（TME）的信号会激活整合应激反应（ISR）——这是一种核心的生存机制，可帮助肿瘤细胞在应激环境下适应并存活增殖。本研究借助单细胞转录组学技术，在携带突变型KRAS且缺失TP53的小鼠LUAD模型（KP模型）的肿瘤组织中，鉴定出了干性与可塑性均较高的细胞簇，这类细胞的ISR通路基因表达水平显著升高。通过敲除磷酸化eIF2α（p-eIF2α）或转录因子ATF4以阻断ISR通路，可抑制LUAD的生长，并阻碍高可塑性、干性相关细胞谱系的产生，最终形成以线粒体功能障碍为特征的独特细胞状态。此外，使用ISRIB（一种低毒性且兼具认知改善功效的小分子ISR抑制剂）进行干预，可促使AT2样LUAD细胞聚集，阻断肿瘤的发育进程与致瘤能力。在人类LUAD中，ISR通路在携带高可塑性与干性特征的KRAS突变型肿瘤中同样呈现激活状态，且与患者不良预后显著相关。上述研究结果表明，ISR是LUAD进展的关键驱动因素，靶向ISR通路或可为延缓LUAD进展、改善肺癌治疗结局提供一种极具潜力的策略。