Immunotherapy resistance in non-small cell lung cancer: from mechanisms to therapeutic opportunities.

IF 12.8 1区 医学 Q1 ONCOLOGY
Huiyu Wang, Xiaomin Niu, Zhenning Jin, Shaoxing Zhang, Rong Fan, Hua Xiao, Shen S Hu
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Abstract

This review provides a comprehensive synthesis of current knowledge on immunotherapy resistance in non-small cell lung cancer (NSCLC), a disease that accounts for approximately 85% of all lung cancer cases and remains the leading cause of cancer-related death worldwide. Although immune checkpoint inhibitors (ICIs) have significantly improved survival for a subset of patients with advanced NSCLC, over 70% of cases ultimately exhibit primary or acquired resistance, underscoring the urgent need to understand the underlying mechanisms. The review categorizes resistance into tumor-intrinsic and tumor-extrinsic processes and provides an in-depth mechanistic analysis of how factors such as tumor antigen loss, impaired antigen presentation, cGAS-STING pathway dysregulation, metabolic reprogramming in tumor microenvironment (TME), immune cell exhaustion, and microbiomes collectively contribute to immune escape. In parallel, the influence of the lung and gut microbiome on shaping immunotherapy responses is discussed, with emphasis on microbial dysbiosis, immunosuppressive metabolite production, and TME remodeling. Therapeutic strategies to overcome resistance are also discussed, including combination approaches involving chemotherapy, radiotherapy, and antiangiogenic agents, as well as epigenetic modulators (HDAC and BET inhibitors). Moreover, the review explores bispecific antibodies, antibody-drug conjugates, and small-molecule agents that enhance T cell function or disrupt immunosuppressive signaling networks. By integrating insights from preclinical models and clinical trials, the review underscores the necessity of biomarker-guided patient stratification, combination immunotherapy approaches, and interventions that restore tumor immunogenicity. It concludes that a multipronged therapeutic strategy, one that addresses both immune evasion and TME-induced suppression, holds the greatest promise for improving response durability and advancing personalized immunotherapy for NSCLC.

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非小细胞肺癌的免疫治疗耐药:从机制到治疗机会。
本文综述了非小细胞肺癌(NSCLC)免疫治疗耐药的最新知识,这种疾病约占所有肺癌病例的85%,并且仍然是全球癌症相关死亡的主要原因。尽管免疫检查点抑制剂(ici)显著提高了部分晚期非小细胞肺癌患者的生存率,但超过70%的病例最终表现出原发性或获得性耐药,这表明迫切需要了解其潜在机制。该综述将耐药分为肿瘤内源过程和肿瘤外源过程,并对肿瘤抗原丢失、抗原呈递受损、cGAS-STING通路失调、肿瘤微环境(TME)代谢重编程、免疫细胞耗竭和微生物组等因素如何共同促进免疫逃逸进行了深入的机制分析。同时,还讨论了肺和肠道微生物组对形成免疫治疗反应的影响,重点是微生物生态失调、免疫抑制性代谢物产生和TME重塑。本文还讨论了克服耐药性的治疗策略,包括联合化疗、放疗、抗血管生成药物以及表观遗传调节剂(HDAC和BET抑制剂)。此外,本文还探讨了双特异性抗体、抗体-药物偶联物和小分子药物,它们可以增强T细胞功能或破坏免疫抑制信号网络。通过整合临床前模型和临床试验的见解,该综述强调了生物标志物引导的患者分层、联合免疫治疗方法和恢复肿瘤免疫原性的干预措施的必要性。结论是,多管齐下的治疗策略,一个解决免疫逃避和tme诱导的抑制,最有希望提高反应的持久性和推进NSCLC的个性化免疫治疗。
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来源期刊
CiteScore
18.20
自引率
1.80%
发文量
333
审稿时长
1 months
期刊介绍: The Journal of Experimental & Clinical Cancer Research is an esteemed peer-reviewed publication that focuses on cancer research, encompassing everything from fundamental discoveries to practical applications. We welcome submissions that showcase groundbreaking advancements in the field of cancer research, especially those that bridge the gap between laboratory findings and clinical implementation. Our goal is to foster a deeper understanding of cancer, improve prevention and detection strategies, facilitate accurate diagnosis, and enhance treatment options. We are particularly interested in manuscripts that shed light on the mechanisms behind the development and progression of cancer, including metastasis. Additionally, we encourage submissions that explore molecular alterations or biomarkers that can help predict the efficacy of different treatments or identify drug resistance. Translational research related to targeted therapies, personalized medicine, tumor immunotherapy, and innovative approaches applicable to clinical investigations are also of great interest to us. We provide a platform for the dissemination of large-scale molecular characterizations of human tumors and encourage researchers to share their insights, discoveries, and methodologies with the wider scientific community. By publishing high-quality research articles, reviews, and commentaries, the Journal of Experimental & Clinical Cancer Research strives to contribute to the continuous improvement of cancer care and make a meaningful impact on patients' lives.
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