CD8⁺ T cell exhaustion is a critical barrier to antitumor immunity. While current research predominantly focuses on tumor microenvironmental regulation of CD8⁺ T cells, intrinsic factors driving exhaustion have been overlooked. The universal exhaustion of CD8⁺ T cells in heterogeneous tumor contexts suggests the existence of conserved intrinsic drivers beyond extrinsic environmental cues. Systematic identification of such universal exhaustion mechanisms and their underlying regulators—conserved across tumor types—could enable broad-spectrum therapeutic strategies targeting multiple cancers.

On January 13, 2025, a collaborative study led by Prof. Peng Jiang (School of Life Sciences, Tsinghua University), Prof. Haichuan Zhu (Wuhan University of Science and Technology), and Prof. Zemin Zhang and Prof. Cheng Li (Peking University) was published in Nature Cancer as a research article titled “ETV7 limits the antiviral and anti-tumor efficacy of CD8⁺ T cells by diverting their fate towards exhaustion”. The study identified the transcription factor ETV7, absent in mice but conserved in human, through screening across 21 tumor types. ETV7 serves as a central driver of CD8⁺ T cell fate transition toward exhaustion and is widely prevalent across various tumor types. Preclinical immunotherapy models demonstrated that targeting ETV7 significantly enhances CAR-T cell efficacy against solid tumors.

To uncover conserved immune evasion mechanisms, the team analyzed scRNA-seq and ATAC-seq data across 21 cancer types, followed by functional screening. This multi-omics approach pinpointed ETV7 as a novel transcriptional factor promoting terminal differentiation of CD8⁺ T cells. Further functional experiment revealed that ETV7 overexpression suppresses tumor-killing and antiviral capacities by accelerating exhaustion.

Mechanistically, ETV7 dynamically binds and transcriptionally regulates key terminal exhaustion genes (e.g., CTLA4, TOX) and memory control genes (e.g., TCF7) during CD8⁺ T cell differentiation. This shifts cellular fate from memory formation to terminal exhaustion, establishing ETV7 as a master regulator of human CD8⁺ T cell exhaustion. In CAR-T therapy models for solid tumors, ETV7 knockdown markedly reduced exhaustion and enhanced antitumor activity, highlighting its therapeutic potential.

Dr. Jie Cheng (PI at Tongji Medical College of HUST), Yifeng Xiao (Tsinghua University), Dr. Ting Peng (Peking University), Dr. Zijian Zhang (Wuhan University of Science and Technology), and Assoc. Prof. You Qin (Huazhong University of Science and Technology) are co-first authors of this paper. Assoc. Prof. Peng Jiang (Tsinghua University), Assoc. Prof. Haichuan Zhu (Wuhan University of Science and Technology), Prof. Zemin Zhang and Cheng Li (Peking University) are the corresponding authors.

Figure 1. Single-cell multi-omics analyses and screening identifies ETV7 as a transcriptional hub driving CD8⁺ T cell terminal differentiation(exhaustion). Targeting ETV7 enhances CAR-T efficacy in solid tumors.

Paper link: https://www.nature.com/articles/s43018-024-00892-0
News release link: https://mp.weixin.qq.com/s/erYb9zddl9-BuFpnU_uUIA