Immune checkpoint blockade therapy has become a major weapon in fighting cancer. Antibody drugs, such as anti-PD-1 and anti-PD-L1, demonstrate obvious advantages such as broad applicability across cancer types and durable clinical response when treatment is effective. However, the overall response rates are still unsatisfying, especially for cancers with low mutational burden. Moreover, adverse effects, such as autoimmune symptoms and tumor hyperprogression, present a significant downside in some clinical applications. These challenges reflect the urgent need to fully understand the basic biology of immune checkpoints. In this review, we discuss regulation of immune checkpoint signaling at multiple levels to provide an overview of our current understanding of checkpoint biology. Topics include the regulation of surface expression levels for known immune checkpoint proteins via surface delivery, internalization, recycling, and degradation. Upon reaching the surface, checkpoints engage in both conventional trans and also cis interactions with ligands to induce signaling and regulate immune responses. Novel therapeutic strategies targeting these pathways in addition to classical checkpoint blockade have recently emerged and been tested in preclinical models, providing new avenues for developing next-generation immunotherapies.

免疫检查点阻断疗法已成为抗击癌症的主要武器。抗体药物，如抗 PD-1 和抗 PD-L1，具有明显的优势，例如对癌症类型的广泛适用性和治疗有效时持久的临床反应。然而，总体反应率仍然不令人满意，特别是对于突变负荷低的癌症。此外，自身免疫症状和肿瘤超进展等不良反应在某些临床应用中存在显着不利影响。这些挑战反映了迫切需要全面了解免疫检查点的基本生物学。在这篇综述中，我们讨论了免疫检查点信号在多个层面的调节，以概述我们目前对检查点生物学的理解。主题包括通过表面递送、内化、回收和降解来调节已知免疫检查点蛋白的表面表达水平。到达水面后，检查站会进行传统的反式也顺相互作用与配体诱导信号和调节免疫反应。除了经典的检查点阻断外，针对这些途径的新治疗策略最近出现并在临床前模型中进行了测试，为开发下一代免疫疗法提供了新的途径。