TCRαβ⁺CD4⁻CD8⁻ double-negative T cells (DNTs) are a subset of T lymphocytes with unique anti-tumor potential, capable of directly killing various hematological malignancies and solid tumor cells. Because allogeneic DNT infusion rarely triggers graft-versus-host disease (GVHD), they hold great promise as a novel off-the-shelf cellular therapeutic product for cancer and have thus garnered considerable attention. However, the intrinsic regulatory mechanisms by which DNT cells maintain their homeostasis and sustain robust, highly efficient tumoricidal activity remain to be elucidated.
To address this gap, a research team led by Professors Dong Zhang and Guangyong Sun at Beijing Chao-Yang Hospital, Capital Medical University, recently published a study in Science China Life Sciences titled “IFITM1 enhances anti-tumor function of unconventional TCRαβ double negative T cells by upregulating mitophagy.” The study reveals that interferon-induced transmembrane protein 1 (IFITM1) promotes mitophagy to preserve mitochondrial homeostasis and maintain DNT anti-tumor activity. These findings provide a strong theoretical framework and a novel intervention target to optimize DNT therapies.
The researchers observed that IFITM1 expression surges upon DNT activation. DNTs with high IFITM1 expression exhibited elevated levels of effector molecules---including granzyme B, perforin, and NKG2D---and achieve superior tumor control in mouse models. Conversely, deleting IFITM1 significantly impairs DNT cytotoxicity, confirming its key role in sustaining anti-tumor efficacy.
Mechanistically, IFITM1 localizes to the mitochondria and interacts with the autophagy receptor protein p62/SQSTM1. By recruiting p62/SQSTM1 to damaged mitochondria, IFITM1 triggers mitophagy, facilitating the prompt clearance of dysfunctional organelles. This quality-control process preserves mitochondrial homeostasis and cellular energy metabolism, supporting sustained tumor killing. Crucially, the team validated this conserved mechanism in human DNTs, highlighting its potential translational significance.
By establishing a clear link among IFITM1, mitophagy, and DNT function, this study underscores the importance of mitochondrial quality control in cell-based cancer treatments. Enhancing IFITM1 expression or modulating its associated mitophagy pathways can improve the metabolic fitness and killing capacity of DNTs, offering a promising strategy for next-generation immunotherapy.
Xiaotong Han and Xiaonan Du from Beijing Chao-Yang Hospital, Capital Medical University, are the co-first authors of the paper. Professor Dong Zhang and Professor Guangyong Sun are the corresponding authors.
Science China Life Sciences