免疫检查点 KLRB1 和 CLEC2D 之间的相互作用对于肿瘤进展和免疫逃避至关重要，但相互作用的动态尚未完全了解。这项研究旨在阐明各种癌症之间的相互作用，并确定可以破坏它的小分子抑制剂。我们对 KLRB1-CLEC2D 对进行全面的泛癌分析，包括 mRNA 表达模式、病理阶段、生存结果和单细胞组学、免疫浸润、拷贝数变异和 DNA 甲基化谱。我们的研究结果表明，与正常组织相比，大多数癌症类型中 CLEC2D/KLRB1 比率始终较高，并且该比率也随着病理阶段的进展而增加。在大多数癌症中，较低的 KLRB1 表达与较高的死亡率相关，这与 CLEC2D 相反。表达变化归因于淋巴细胞浸润差异、CNV 和 DNA 甲基化。基于结构的虚拟筛选分析确定了包括连翘酯苷 A 和 RGD 肽在内的化合物作为 KLRB1-CLEC2D 相互作用的有效抑制剂，并通过微尺度热泳进行验证。这项研究增进了对肿瘤微环境中 KLRB1-CLEC2D 相互作用的理解，并引入了调节这种相互作用的新治疗策略。版权所有 © 2024。由 Elsevier B.V. 出版。

The interplay between immune checkpoints KLRB1 and CLEC2D is crucial for tumor progression and immune evasion, yet the interaction dynamics are not fully understood. This study aims to elucidate the interaction across various cancers and identify small molecule inhibitors that can disrupt it. We perform a comprehensive pan-cancer analysis of the KLRB1-CLEC2D pair, including mRNA expression patterns, pathological stages, survival outcomes, and single-cell omics, immune infiltration, copy number variations, and DNA methylation profiles. Our findings reveal a consistently higher CLEC2D/KLRB1 ratio in most cancer types compared to normal tissues, and this ratio also increased with advancing pathological stages. Lower KLRB1 expression correlated with higher mortality in most cancers, opposite to CLEC2D. Expression variations were attributed to differential lymphocyte infiltration, CNV, and DNA methylation. Structure-based virtual screening analysis identified compounds including forsythiaside A and RGD peptides as effective inhibitors of the KLRB1-CLEC2D interaction, validated through microscale thermophoresis. This research advances understanding of the KLRB1-CLEC2D interaction within the tumor microenvironment and introduces novel therapeutic strategies to modulate this interaction.Copyright © 2024. Published by Elsevier B.V.