近年来，引入针对免疫检查点的单克隆抗体以调节抗肿瘤免疫反应的方法，使癌症治疗格局发生了革命性变化。免疫检查点阻断（ICB）疗法的治疗成功主要依赖于PD-1/PD-L1和CTLA-4的阻断。然而，总体反应的限制和缺乏可靠的患者预测反应的生物标志物是限制免疫治疗成功的主要缺陷。因此，这反映了揭示免疫治疗新靶点的迫切需求，以扩展ICB策略的范围，以实现最佳的治疗疗效和对癌症患者的益处。本综述全面剖析了当前BTLA/HVEM轴的分子和功能知识，并探讨其作为癌症免疫治疗靶点的未来展望。BTLA/HVEM失调在实体和血液恶性肿瘤中常见，并与不良预后有关。此外，循环的BTLA已被证实为各种癌症免疫治疗反应的血液生物标志物。基于此，BTLA/HVEM轴成为癌症免疫治疗的一个新的有前景的靶点。这促使了抗BTLA阻断抗体Tifcemalimab/icatolimab的快速发展和临床试验，作为第一个针对BTLA的治疗方法，参与了多个进行中的I期临床试验，并在单药和与其他抗PD-1/PD-L1疗法联合治疗中取得了令人鼓舞的初步疗效和安全性结果。然而，BTLA/HVEM/CD160/LIGHT所涉及的复杂信号网络在免疫反应的调节、肿瘤发展和肿瘤微环境中可能限制治疗成功。因此，强烈建议在不同癌症环境中进行深入的功能特性鉴定，以确保对癌症患者获得最佳的临床结果。Copyright 2023 BioMed Central Ltd., part of Springer Nature.

Recent introduction of monoclonal antibodies targeting immune checkpoints to harness antitumor immunity has revolutionized the cancer treatment landscape. The therapeutic success of immune checkpoint blockade (ICB)-based therapies mainly relies on PD-1/PD-L1 and CTLA-4 blockade. However, the limited overall responses and lack of reliable predictive biomarkers of patient´s response are major pitfalls limiting immunotherapy success. Hence, this reflects the compelling need of unveiling novel targets for immunotherapy that allow to expand the spectrum of ICB-based strategies to achieve optimal therapeutic efficacy and benefit for cancer patients. This review thoroughly dissects current molecular and functional knowledge of BTLA/HVEM axis and the future perspectives to become a target for cancer immunotherapy. BTLA/HVEM dysregulation is commonly found and linked to poor prognosis in solid and hematological malignancies. Moreover, circulating BTLA has been revealed as a blood-based predictive biomarker of immunotherapy response in various cancers. On this basis, BTLA/HVEM axis emerges as a novel promising target for cancer immunotherapy. This prompted rapid development and clinical testing of the anti-BTLA blocking antibody Tifcemalimab/icatolimab as the first BTLA-targeted therapy in various ongoing phase I clinical trials with encouraging results on preliminary efficacy and safety profile as monotherapy and combined with other anti-PD-1/PD-L1 therapies. Nevertheless, it is anticipated that the intricate signaling network constituted by BTLA/HVEM/CD160/LIGHT involved in immune response regulation, tumor development and tumor microenvironment could limit therapeutic success. Therefore, in-depth functional characterization in different cancer settings is highly recommended for adequate design and implementation of BTLA-targeted therapies to guarantee the best clinical outcomes to benefit cancer patients.© 2023. BioMed Central Ltd., part of Springer Nature.