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.
ZUO et al. (Mon,) studied this question.