Zhao Shen, Zhao Hongyun, Yang Weiwei, Zhang Li
Department of Medical Oncology, Sun Yat-sen University Cancer Centre, State Key Laboratory of Oncology in South China, Collaborative Innovation Centre for Cancer Medicine, Guangdong Provincial Clinical Research Centre for Cancer, Guangzhou, China.
Department of Clinical Research, Sun Yat-sen University Cancer Centre, State Key Laboratory of Oncology in South China, Collaborative Innovation Centre for Cancer Medicine, Guangdong Provincial Clinical Research Centre for Cancer, Guangzhou, China.
Nat Rev Clin Oncol. 2025 Jun 17. doi: 10.1038/s41571-025-01035-9.
Immunotherapies, specifically immune-checkpoint inhibitors (ICIs) targeting PD-(L)1 or CTLA4, have revolutionized the treatment of lung cancer; however, many patients do not have a response to ICIs and most of those with an initial tumour response eventually have disease progression owing to acquired resistance. Over the past few years, numerous therapeutic strategies have been explored to address the problems of intrinsic and acquired resistance to ICIs. In 2024, regulatory approvals of the bispecific PD-1 × VEGF antibody ivonescimab for the treatment of non-small-cell lung cancer in China and the bispecific DLL3 × CD3 T cell engager tarlatamab for patients with small cell lung cancer in the USA provided clinical proof-of-concept for overcoming the challenge of ICI resistance using novel immunotherapeutic agents, thereby increasing enthusiasm for the exploration of next-generation immunotherapies for lung cancer. A large variety of immunotherapies with diverse targets and mechanisms of action are currently being tested in clinical trials involving patients with lung cancer. In this Review, we provide an overview of these emerging immunotherapies in clinical development for non-small-cell lung cancer and/or small cell lung cancer, including novel immune-checkpoint modulators, immune cell engagers, adoptive cell therapies and therapeutic cancer vaccines. We describe the designs of these agents and the mechanisms by which they might overcome resistance to the current generation of ICIs. We also discuss hurdles impeding the clinical translation of each immunotherapeutic modality and potential strategies to address these challenges, using representative examples of agents that have entered the later phases of clinical testing.
免疫疗法，特别是针对PD-(L)1或CTLA4的免疫检查点抑制剂（ICI），彻底改变了肺癌的治疗方式；然而，许多患者对ICI没有反应，而且大多数最初有肿瘤反应的患者最终会因获得性耐药而出现疾病进展。在过去几年中，人们探索了众多治疗策略来解决对ICI的固有耐药和获得性耐药问题。2024年，双特异性PD-1×VEGF抗体艾沃西单抗在中国获批用于治疗非小细胞肺癌，双特异性DLL3×CD3 T细胞衔接器他拉塔单抗在美国获批用于治疗小细胞肺癌患者，这为使用新型免疫治疗药物克服ICI耐药挑战提供了临床概念验证，从而增加了对探索肺癌下一代免疫疗法的热情。目前，多种具有不同靶点和作用机制的免疫疗法正在涉及肺癌患者的临床试验中进行测试。在本综述中，我们概述了这些正在临床开发用于非小细胞肺癌和/或小细胞肺癌的新兴免疫疗法，包括新型免疫检查点调节剂、免疫细胞衔接器、过继性细胞疗法和治疗性癌症疫苗。我们描述了这些药物的设计及其可能克服对当前一代ICI耐药的机制。我们还讨论了阻碍每种免疫治疗方式临床转化的障碍以及应对这些挑战的潜在策略，并列举了已进入临床测试后期阶段的药物的代表性例子。
