嵌合抗原受体T细胞（CAR-T）被视为治疗恶性肿瘤的有前途的疗法。在我们早期针对结肠癌的临床试验中，我们发现CAR-T细胞在肿瘤部位的增殖和持续性较差。为了提高CAR-T细胞的效力，我们将CD27协同刺激信号引入已有的系统，发现CEA28BB27Z CAR-T细胞表现出增强的增殖和抗肿瘤活性。接下来，我们证明了CEA28BB27Z CAR-T细胞在持续抗原刺激期间表达较少的免疫检查点受体，并产生更多的CD4+和CD8+记忆干细胞T（TSCM）细胞，与其他CAR相比，更有效。此外，我们的数据显示不同的协同刺激信号组合影响CAR-T细胞的线粒体动力学，CEA28BB27Z CAR-T细胞与其他细胞相比保持更多的融合线粒体网络。最后，我们验证了CEA28BB27Z CAR-T细胞在异种移植模型中更优越的抗肿瘤能力。我们的发现表明，CD27协同刺激信号在提高CAR-T细胞的抗肿瘤效力方面起着关键作用。 ©2023作者，属于Springer Nature旗下的Springer Science+Business Media，LLC的独家许可。

Chimeric antigen receptor T cell (CAR-T) is regarded as a promising therapy for malignancies. In our previous clinical trial targeted colorectal tumors, we found that CAR-T cells experienced poor proliferation and persistence in tumor sites. To improve the efficacy of CAR-T cells, we introduced CD27 co-stimulation signal into the established system and found that the CEA28BB27Z CAR-T cells exhibited enhanced proliferation and anti-tumor activity. Next, we demonstrated that the CEA28BB27Z CAR-T cells expressed less immune checkpoint receptors and generated more CD4+ and CD8+ memory stem T (TSCM) cells compared with other CARs during constant antigen stimulation. Furthermore, our data revealed that the different combination of co-stimulation signal affected the mitochondrial dynamics of CAR-T cells, and CEA28BB27Z CAR-T cells maintained more fused mitochondrial network compared with others. Finally, we validated the superior antitumor capacity of the CEA28BB27Z CAR-T cells in xenograft models. Our findings suggest that CD27 co-stimulation signals play a key role in improving the anti-tumor efficacy of CAR-T cells.© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.