The loss of T cell effector function in the tumor microenvironment is one of the main reasons for immunotherapy failure. Metabolic adaptation plays an important regulatory role in T cell function and fate. Studies have shown that mitochondrial metabolism is influenced by various mitochondrial behaviours, including mitochondrial fusion and mitochondria-endoplasmic reticulum (ER) contact. However, little is known about the characteristics and significance of mitochondrial behaviour in tumor infiltrating CD8⁺T cells (TILs).

In order to reveal mitochondrial behaviour in TILs and the related molecular mechanism of metabolic adaptation, the research team led by Prof. Gao Song, Prof. Han Hui from Sun Yat-sen University Cancer Center (SYSUCC), and Prof. Bai Fan from Peking University conducted in-depth cooperation in this interesting research topic. Through various techniques such as clinical specimen validation, single cell sequencing, transgenic mouse models, cell biology and biochemistry, the significance of mitochondria-ER contact by MFN2 in CD8⁺ TIL has been revealed, as well as its key role in the metabolic adaptation and anti-tumor effects of CD8⁺ T cells in the tumor microenvironment, providing theoretical foundations for immunotherapy innovation. Further, a new strategy to improve tumor immunotherapy efficacy by increasing MFN2 levels has been proposed. On September 22, 2023, their research achievement was published in Science Immunology, entitled "Mitochondria-ER contact mediated by MFN2-SERCA2 interaction supports CD8⁺ T cell metabolic fitness and function in tumors".

Prof. Gao Song from the Department of Experimental Research of SYSUCC, Prof. Han Hui from the Urology Department of SYSUCC and Prof. Bai Fan from the Biomedical Pioneering Innovation Center (BIOPIC) of Peking University, shared co-corresponding authorship of the paper. Dr. Yang Jie-Feng, Dr. Luo Li from SYSUCC, Dr. Xing Xudong from BIOPIC, and graduate student Zhou Xinwei from the First Affiliated Hospital of Sun Yat-sen University are the co-first authors of this article. This research has been supported by grants including the National Key R&D Program, the National Natural Science Foundation of China, and Natural Science Foundation of Guangdong Province.

Prof. Gao Song’s research group is committed to studying the mechanism of mitochondrial fusion and its significance in tumor invasion and metastasis, through multidisciplinary approaches. In previous studies, they have solved the crystal structures of mitochondrial outer membrane fusion proteins MFN1 and MFN2, and revealed their roles in membrane fusion (Nature 2017; Nature Communications 2019; Trends in Cell Biology 2021).

Link to the article on Science Immunology journal

https://www.science.org/doi/10.1126/sciimmunol.abq2424

Written by: Liao Shuang, Gao Song