T cells play a critical role in promoting tumor regression in both experimental models and humans. Yet, T cells that are chronically exposed to tumor antigen during cancer progression can become dysfunctional/exhausted and fail to induce tumor destruction. Such tumor-induced T cell dysfunction may occur via multiple mechanisms. In particular, immune checkpoint inhibitory receptors that are upregulated by tumor-infiltrating lymphocytes in many cancers limit T cell survival and function. Overcoming this inhibitory receptor-mediated T cell dysfunction has been a central focus of recent developments in cancer immunotherapy. Immunotherapies targeting inhibitory receptor pathways such as programmed cell death 1 (PD-1)/programmed death ligand 1 and cytotoxic T lymphocyte-associated antigen 4 (CTLA-4), alone or in combination, confer significant clinical benefits in multiple tumor types. However, many patients with cancer do not respond to immune checkpoint blockade, and dual PD-1/CTLA-4 blockade may cause serious adverse events, which limits its indications. Targeting novel non-redundant inhibitory receptor pathways contributing to tumor-induced T cell dysfunction in the tumor microenvironment may prove efficacious and non-toxic. This review presents preclinical and clinical findings supporting the roles of two key pathways—T-cell immunoglobulin and mucin-domain containing-3 (TIM-3) and T cell immunoreceptor with Ig and ITIM domain (TIGIT)/CD226/CD96/CD112R—in cancer immunotherapy.

T 细胞在促进实验模型和人类的肿瘤消退方面发挥着关键作用。然而，在癌症进展过程中长期暴露于肿瘤抗原的 T 细胞可能会变得功能失调/精疲力竭并且无法诱导肿瘤破坏。这种肿瘤诱导的 T 细胞功能障碍可能通过多种机制。特别是，在许多癌症中被肿瘤浸润淋巴细胞上调的免疫检查点抑制受体限制了 T 细胞的存活和功能。克服这种抑制性受体介导的 T 细胞功能障碍一直是癌症免疫疗法近期发展的中心焦点。针对抑制性受体通路的免疫疗法，如程序性细胞死亡 1 (PD-1)/程序性死亡配体 1 和细胞毒性 T 淋巴细胞相关抗原 4 (CTLA-4)，单独或联合使用，可在多种肿瘤类型中带来显着的临床益处。然而，许多癌症患者对免疫检查点阻断没有反应，双重PD-1/CTLA-4阻断可能会导致严重的不良事件，从而限制了其适应症。在肿瘤微环境中靶向导致肿瘤诱导的 T 细胞功能障碍的新型非冗余抑制性受体通路可能被证明是有效且无毒的。本综述介绍了支持两种关键途径的临床前和临床发现——T 细胞免疫球蛋白和含有粘蛋白结构域的 3 (TIM-3) 和具有 Ig 和 ITIM 结构域的 T 细胞免疫受体 (TIGIT)/CD226/CD96/CD112R——在癌症免疫治疗中。