The Tumor Microenvironment Imposes Persistent ATF4 in CD8+ TILs to Obstruct Cancer Control

The T cell-intrinsic element that responds to tumor microenvironment (TME) stress to shape CD8+ tumor infiltrating lymphocyte (TIL) fate and function in solid cancers remains elusive. Here we report that the hypoxic TME imprints persistent activity of the central transcriptional node of the integrated stress response (ISR), activating transcription factor 4 (ATF4), in CD8+ TILs that results in metabolic polarity, mitochondrial oxidative stress, and cell death. Chronic ATF4 expression replicated the terminal exhaustion cell state in CD8+ T cells and high Atf4 expression in bulk tumor or peripheral T cells of patients with melanoma predicted poor response to PD-1 inhibition. Genetic or pharmacologic attenuation of ATF4 reduced mitochondrial oxidative stress and promoted viability among CD8+ TILs, enabling complete responses to PD-1 inhibition and conferring protection from re-emergent disease. Our multidisciplinary approach identifies chronic ATF4 activity as a barrier to immune checkpoint inhibitors, positioning ISR therapeutics as novel treatment strategies to improve efficacy of immunotherapy combinations. RNA-seq data from CD8+ T cells isolated from spleens of naïve ATF4Tg/Tg or E8IcreATF4Tg/Tg mice

实体瘤中，响应肿瘤微环境（tumor microenvironment, TME）应激并调控CD8+肿瘤浸润淋巴细胞（CD8+ tumor infiltrating lymphocyte, TIL）命运与功能的T细胞固有元件，其分子机制仍未明确。本研究发现，缺氧的肿瘤微环境会在CD8+ TIL中诱导整合应激反应（integrated stress response, ISR）核心转录节点的持续活化，激活激活转录因子4（activating transcription factor 4, ATF4），进而引发代谢极性异常、线粒体氧化应激及细胞死亡。长期过表达ATF4可复刻CD8+ T细胞的终末耗竭细胞状态；黑色素瘤患者实体瘤整体组织或外周血T细胞中高表达Atf4，提示其对PD-1阻断疗法的响应不佳。通过遗传或药理学手段抑制ATF4，可减轻CD8+ TIL中的线粒体氧化应激并提升其存活率，使肿瘤对PD-1阻断疗法产生完全响应，同时可预防疾病复发。本研究采用多学科研究方法，证实长期ATF4活化是免疫检查点抑制剂治疗的阻碍因素，并提示整合应激反应靶向疗法可作为提升免疫联合治疗疗效的新型治疗策略。本数据集所用的RNA测序（RNA-seq）数据，采自从未致敏ATF4Tg/Tg或E8IcreATF4Tg/Tg小鼠脾脏中分离的CD8+ T细胞。