《生命科学》 2026, 38(4): 708-720

基于肺癌免疫治疗的三特异性抗体的研究进展

左梓谦^1,2 , 刘亚岚^1,3 , 陈 鹏^1,*

¹天津医科大学肿瘤医院，国家恶性肿瘤临床医学研究中心，天津市肿瘤防治重点实验室，肺部肿瘤内科，天津 300060 ²天津医科大学，天津 300041 ³湖南省邵阳市中心医院肿瘤内科，邵阳 422000

摘　要：

肺癌是全球癌症死亡的首要病因，尽管肺癌免疫疗法已取得进展，但其临床响应率低、耐药性高及免疫逃逸等问题仍亟待解决。三特异性抗体（trispecific antibodies，TsAbs）通过三重靶点协同作用进一步提升了抗体疗效和安全性，在肺癌治疗中展现出突破现有瓶颈的巨大潜能。本文综述了TsAbs的构建模块及其在肺癌中的最新研究进展，重点探讨了其功能分类和临床转化动态。然而，TsAbs正面临免疫原性、免疫抑制性肿瘤微环境及精准靶向优化等方面的挑战。未来的研究方向应聚焦于抗体结构创新、条件激活性设计及四特异性抗体的探索，以推动TsAbs在肺癌治疗中的临床转化，为实现高效低毒的精准免疫治疗提供新策略。

通讯作者：陈 鹏 , Email:chenpengdoc@sina.com

Research progress of tri-specific antibodies based on immunotherapy for lung cancer

ZUO Zi-Qian^1,2 , LIU Ya-Lan^1,3 , CHEN Peng^1,*

¹Department of Thoracic Oncology, Tianjin Key Laboratory of Cancer Prevention and Therapy, National Clinical Research Center for Cancer, Tianjin Medical University Cancer Institute & Hospital, Tianjin 300060, China ²Tianjin Medical University, Tianjin 300041, China ³Department of Medical Oncology, Shaoyang Central Hospital, Shaoyang 422000, China

Abstract:

Lung cancer remains the leading cause of cancer-related mortality globally. Although immunotherapy has brought revolutionary advances to the treatment of lung cancer, significant challenges—such as low clinical response rates, high rates of primary and acquired resistance, and immune evasion—persist and underscore the urgent need for next-generation therapeutic strategies. In recent years, trispecific antibodies (TsAbs), which leverage synergistic targeting of three distinct antigens, have demonstrated breakthrough potential in achieving more precise immune activation while enhancing both efficacy and safety. This article systematically reviews the development and current landscape of TsAbs in lung cancer immunotherapy, highlighting their capacity to overcome limitations inherent to conventional monospecific and bispecific antibody approaches. The review begins by introducing the structural modules of TsAbs, which are broadly categorized into two formats: non-IgG-like formats designed to improve tumor penetration and reduce Fc-mediated toxicity, and IgG-like formats that retain Fc-dependent effector functions and exhibit extended serum halflife. Then, it provides a detailed overview of the functional classifications and clinical translation progress of TsAbs under investigation for lung cancer. These include T cell engagers, NK cell engagers, TsAbs targeting three tumor-associated antigens, and immune checkpoint inhibitors. Preclinical and earlyphase clinical data indicated that TsAbs could mediate potent tumor killing, mitigate common escape mechanisms, and remodel the immunosuppressive tumor microenvironment. Several candidates have already shown encouraging safety and efficacy profiles in Phase I/II trials. Despite these promising advances, TsAbs still face considerable challenges in clinical translation. Key hurdles include immunogenicity risks, manufacturing complexity, ontarget offtumor toxicities, and the highly heterogeneous and adaptive nature of the tumor microenvironment. Looking forward, we propose that future efforts should focus on innovative target combinations, structural optimization of antibody architectures, dynamic adaptation to the tumor microenvironment, and the exploration of tetraspecific antibody platforms. Through these strateges, TsAbs are poised to advance clinical translation in lung cancer therapy, offering new avenues for achieving highly effective, low toxicity, and precision immunotherapy.

Communication Author：CHEN Peng , Email:chenpengdoc@sina.com