On June 18, 2025, the research group led by Prof. LU Wei from the Shanghai Institute of Nutrition and Health (SINH), Chinese Academy of Sciences (CAS), jointly published a research paper titled "CARD11 signaling regulates CD8⁺T cell tumoricidal function" online in the journal Nature Immunology, in collaboration with domestic and international partners.

This study utilized T cell receptor (TCR) signaling protein CARD11 mutants derived from immunodeficient patients to construct Card11 gene mutant mice, thereby revealing the in vivo relationship between TCR signaling intensity and the differentiation of T cell exhaustion in tumors. It suggests that regulating the TCR signaling intensity mediated by CARD11 can alter the clonal diversity of anti-tumor CD8 T cells in the tumor microenvironment and enhance the anti-tumor immune response, providing a new approach for cancer immunotherapy.

CD8⁺ T cells in the tumor microenvironment undergo continuous stimulation by tumor antigens, leading to the differentiation of these cells into exhausted CD8⁺ T cells (Tex). Exhausted differentiation has long been considered a major factor that leads to tumor escape from immune surveillance. However, recent studies have shown that Tex still possesses some anti-tumor capabilities, but its functionality is constrained by the low antigenicity of tumors and multiple immunosuppressive receptors. Therefore, in-depth exploration of the molecular mechanisms behind Tex differentiation is of great significance for developing more effective tumor immunotherapy strategies.

To this end, researchers established tumor models based on various CARD11 mutant transgenic mice. The results indicated that overly high CARD11 signaling intensity downstream of the TCR in CD8⁺ T cells blocked the differentiation of CD8⁺ T cells into an exhausted state in the tumor microenvironment. In contrast, a relatively moderate TCR signaling intensity promoted the accumulation of Tex differentiation within tumors.

The research team further sorted tumor-infiltrating CD8⁺ T cells for in vitro cytotoxicity experiments, confirming that Tex has a strong tumor cell-killing function. However, single-cell TCR sequencing of Tex revealed that such populations exhibited high oligoclonality, with significantly limited diversity in their TCR repertoire. This means that Tex can only recognize a very limited range of tumor antigens. The continuous mutations and evolution of tumors leading to antigen escape ultimately prevent Tex from effectively eliminating tumors.

Finally, the researchers further elucidated how CARD11, as a scaffolding protein, regulates the intracellular transport and degradation of the TCR complex by sensing the intensity of upstream TCR signaling, thereby determining the differentiation fate of CD8 T cells. This research reveals a negative correlation between TCR signaling intensity and Tex differentiation, demonstrating that the limitation in tumor antigen recognition diversity may be a key reason why Tex is unable to eliminate tumors.

Prof. Michael J. Lenardo from the National Institutes of Health, USA; Prof. ZHANG Yan from Shanghai Jiao Tong University School of Medicine; Prof. ZHANG Peng from the Beijing Children's Research Institute; and Prof. LI Hecheng from Ruijin Hospital affiliated to Shanghai Jiao Tong University School of Medicine, are the co-corresponding authors of the article. Dr. HU Yu and Dr. ZHAO Qifan from SINH, along with doctoral student QIN Yingquan and Dr. MEI Song from Shanghai Jiao Tong University School of Medicine, are the co-first authors of the paper. This research was supported by the National Natural Science Foundation of China and the Collaborative Innovation Center of Shanghai Institute of Nutrition and Health, Shanghai Jiao Tong University School of Medicine.

CARD11 signaling regulates CD8⁺ T cell tumoricidal function. (Image provided by Prof. LU’s group)

Paper Link：https://doi.org/10.1038/s41590-025-02192-w

Scientific Contact:

Prof. LU Wei

Shanghai Institute of Nutrition and Health,

Chinese Academy of Sciences

Email: lvwei@sinh.ac.cn

Media Contact:

WANG Jin

Shanghai Institute of Nutrition and Health,

Chinese Academy of Sciences

Email: wangjin01@sinh.ac.cn

Web: http://english.sinh.cas.cn/