靶向TNF-TNFR2轴的抗体治疗以克服肿瘤免疫抵抗
Antibody targeting of the TNF-TNFR2 axis to overcome tumor immune resistance.
摘要(中文译文)
肿瘤坏死因子（TNF）在癌症中发挥矛盾性作用，这源于其两个受体TNFR1和TNFR2的差异性激活。虽然TNFR1介导细胞毒性信号，但越来越多的证据表明，TNFR2主要在肿瘤微环境（TME）中协调促肿瘤炎症和免疫抑制。TNFR2在调节性T细胞（Tregs）、髓源性抑制细胞（MDSCs）、癌症相关成纤维细胞（CAFs）和恶性细胞上高表达，形成一个协调网络，驱动免疫逃逸并促进对免疫检查点阻断（ICB）的耐药。在本综述中，我们剖析跨膜型与可溶性TNF之间的结构和功能差异，并讨论这些差异如何塑造受体特异性信号转导结果。我们进一步重点介绍靶向TNF-TNFR2轴的新兴治疗策略，包括单克隆抗体、抗体药物偶联物（ADCs）和双特异性抗体，重点阐述其选择性重塑免疫抑制性TME的能力。最后，我们讨论临床转化的关键挑战，包括靶向毒性、患者分层和情境依赖性TNFR2生物学，并概述未来方向，如生物标志物引导的治疗和肿瘤限制性靶向策略。总之，这些进展使TNFR2成为克服当前免疫治疗耐药的有前景的治疗节点。
Abstract
Tumor necrosis factor (TNF) exerts paradoxical effects in cancer, driven by the differential engagement of its two receptors, TNFR1 and TNFR2. While TNFR1 mediates cytotoxic signaling, accumulating evidence indicates that TNFR2 predominantly orchestrates tumor-promoting inflammation and immunosuppression within the tumor microenvironment (TME). TNFR2 is highly expressed on regulatory T cells (Tregs), myeloid-derived suppressor cells (MDSCs), cancer-associated fibroblasts (CAFs), and malignant cells, forming a coordinated network that drives immune evasion and contributes to resistance to immune checkpoint blockade (ICB). In this review, we dissect the structural and functional distinctions between transmembrane and soluble TNF and discuss how these differences shape receptor-specific signaling outcomes. We further highlight emerging therapeutic strategies targeting the TNF-TNFR2 axis, including monoclonal antibodies, antibody-drug conjugates (ADCs), and bispecific antibodies, with an emphasis on their ability to selectively remodel the immunosuppressive TME. Finally, we discuss key challenges for clinical translation, including on-target toxicity, patient stratification, and context-dependent TNFR2 biology, and outline future directions such as biomarker-guided therapy and tumor-restricted targeting approaches. Together, these advances position TNFR2 as a promising therapeutic node for overcoming resistance to current immunotherapies.
如何引用
AMA
Xiaozhen Kang, Xiangmin Tong, Shibing Wang. Antibody targeting of the TNF-TNFR2 axis to overcome tumor immune resistance.. Frontiers in immunology. 2026; doi:10.3389/fimmu.2026.1809305.
APA
Xiaozhen Kang, Xiangmin Tong, Shibing Wang (2026). Antibody targeting of the TNF-TNFR2 axis to overcome tumor immune resistance.. Frontiers in immunology. https://doi.org/10.3389/fimmu.2026.1809305
GB/T 7714
Xiaozhen Kang, Xiangmin Tong, Shibing Wang. Antibody targeting of the TNF-TNFR2 axis to overcome tumor immune resistance.[J]. Frontiers in immunology, 2026 doi:10.3389/fimmu.2026.1809305.
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