在肺癌免疫逃避中拮抗抗肿瘤先天免疫途径的负调节因子
Negative regulators antagonizing antitumor innate immune pathways in lung cancer immune evasion.
摘要(中文译文)
先天免疫感知系统是识别肿瘤相关异常核酸并启动抗肿瘤免疫应答的关键防线，在肺癌的发生、进展及治疗反应中发挥重要作用。近年研究表明，在基因组不稳定、线粒体损伤、表观遗传失调及治疗诱导的应激等条件下，肺癌细胞可释放多种异常DNA、RNA及损伤相关分子模式（DAMPs），从而激活包括cGAS-STING、Toll样受体（TLR）及RIG-I样受体（RLR）信号通路在内的关键先天免疫通路。这些通路通过诱导I型干扰素、炎性细胞因子及趋化因子，调控树突状细胞、自然杀伤细胞、中性粒细胞、巨噬细胞及T细胞等多种免疫细胞群体的募集、活化与功能分化，从而塑造肺癌的抗肿瘤免疫网络。然而，在长期演化过程中，肺癌通过遗传改变、表观遗传修饰、泛素介导的蛋白降解、代谢重编程及非编码RNA调控等多层次免疫抑制机制抑制先天免疫信号传导。这些过程损害抗原提呈、限制效应淋巴细胞浸润，并促进肿瘤相关巨噬细胞、髓源性抑制细胞及调节性T细胞等免疫抑制细胞群体的积聚，最终导致免疫逃逸。本综述全面讨论肺癌中三大先天免疫通路——cGAS-STING、TLR及RLR信号通路——的激活机制、肿瘤介导的负性调控机制及其对肿瘤免疫微环境的影响。此外，还讨论靶向这些通路在免疫治疗中的潜在临床价值，旨在为优化肺癌免疫治疗策略及设计联合干预方案提供理论依据。
Abstract
The innate immune sensing system serves as a critical line of defense for recognizing tumor-associated abnormal nucleic acids and initiating antitumor immune responses, and it plays an essential role in lung cancer development, progression, and therapeutic response. Recent studies have shown that, under conditions such as genomic instability, mitochondrial damage, epigenetic dysregulation, and therapy-induced stress, lung cancer cells can release a variety of abnormal DNA, RNA, and damage-associated molecular patterns (DAMPs), thereby activating key innate immune pathways, including cGAS-STING, Toll-like receptor (TLR), and RIG-I-like receptor (RLR) signaling. These pathways regulate the recruitment, activation, and functional differentiation of multiple immune cell populations, including dendritic cells, natural killer cells, neutrophils, macrophages, and T cells, through the induction of type I interferons, inflammatory cytokines, and chemokines, thereby shaping an antitumor immune network in lung cancer. However, during long-term evolution, lung cancer develops multilayered immunosuppressive mechanisms that inhibit innate immune signaling through genetic alterations, epigenetic modifications, ubiquitin-mediated protein degradation, metabolic reprogramming, and non-coding RNA regulation. These processes impair antigen presentation, restrict effector lymphocyte infiltration, and promote the accumulation of immunosuppressive cell populations such as tumor-associated macrophages, myeloid-derived suppressor cells, and regulatory T cells, ultimately leading to immune evasion. This review comprehensively discusses the activation mechanisms of three major innate immune pathways in lung cancer-cGAS-STING, TLR, and RLR signaling-the tumor-mediated negative regulatory mechanisms that suppress them, and their impact on the tumor immune microenvironment. Furthermore, it discusses the potential clinical value of targeting these pathways in immunotherapy, with the aim of providing a theoretical basis for optimizing lung cancer immunotherapeutic strategies and designing combination interventions.
如何引用
AMA
Fan Yang, Rui Liu, Li Liu, Aijie Zhang, Bo Li. Negative regulators antagonizing antitumor innate immune pathways in lung cancer immune evasion.. Frontiers in immunology. 2026; doi:10.3389/fimmu.2026.1842558.
APA
Fan Yang, Rui Liu, Li Liu, Aijie Zhang, Bo Li (2026). Negative regulators antagonizing antitumor innate immune pathways in lung cancer immune evasion.. Frontiers in immunology. https://doi.org/10.3389/fimmu.2026.1842558
GB/T 7714
Fan Yang, Rui Liu, Li Liu, Aijie Zhang, Bo Li. Negative regulators antagonizing antitumor innate immune pathways in lung cancer immune evasion.[J]. Frontiers in immunology, 2026 doi:10.3389/fimmu.2026.1842558.
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