免疫检查点分子的失调表达使癌细胞能够逃避免疫破坏。尽管抑制性免疫检查点如PD-L1的阻断形成了当前癌症免疫治疗的基础，但刺激性信号的不足可能使这些疗法无效。CD58作为一个刺激性配体，在抗肿瘤免疫反应中起着关键作用，但其表达的调控机制尚不清楚。通过两种系统性方法，我们揭示了CMTM6对CD58表达的正调控作用。值得注意的是，CMTM6与CD58和PD-L1都有相互作用，维持着具有相反功能的这两个免疫检查点配体的表达。在功能上，肿瘤细胞上CMTM6和CD58的存在显著影响了T细胞-肿瘤细胞的相互作用和对PD-L1-PD-1阻断的反应。总的来说，这些发现为CD58的调控提供了基础见解，揭示了刺激性和抑制性免疫检查点的共享调节因子，并强调了肿瘤内在CMTM6和CD58表达在抗肿瘤免疫反应中的重要性。版权所有 © 2023 作者。由Elsevier公司出版。保留所有权利。

The dysregulated expression of immune checkpoint molecules enables cancer cells to evade immune destruction. While blockade of inhibitory immune checkpoints like PD-L1 forms the basis of current cancer immunotherapies, a deficiency in costimulatory signals can render these therapies futile. CD58, a costimulatory ligand, plays a crucial role in antitumor immune responses, but the mechanisms controlling its expression remain unclear. Using two systematic approaches, we reveal that CMTM6 positively regulates CD58 expression. Notably, CMTM6 interacts with both CD58 and PD-L1, maintaining the expression of these two immune checkpoint ligands with opposing functions. Functionally, the presence of CMTM6 and CD58 on tumor cells significantly affects T cell-tumor interactions and response to PD-L1-PD-1 blockade. Collectively, these findings provide fundamental insights into CD58 regulation, uncover a shared regulator of stimulatory and inhibitory immune checkpoints, and highlight the importance of tumor-intrinsic CMTM6 and CD58 expression in antitumor immune responses.Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.