The harsh conditions of the tumor microenvironment often push CD8+ T cells into a state of terminal exhaustion, which is characterized by an accumulation of dysfunctional mitochondria and extensive genetic reprogramming. Researchers led by Ludwig Lausanne’s Yingxi Xu and Ping-Chih Ho reported in a March paper in Nature how the accumulation of depolarized mitochondria drives terminal exhaustion through processes involving the release of the iron-bearing compound heme. They showed that the glut of dysfunctional mitochondria seen in exhausted tumor infiltrating CD8+ T cells enhances proteasome activity that preferentially degrades mitochondrial heme-containing proteins. The resulting intracellular buildup of heme leads to the generation of a functionally distinct form of the molecule known as regulatory heme, which shuttles into the nucleus via the nuclear transporter PGRMC. There it binds the transcription factor BACH2, inducing its degradation and awakening gene expression programs that drive terminal exhaustion. The researchers showed that disruption of PGRMC2 abrogates this effect, keeping anti-tumor T cells in a functionally vibrant state. They also demonstrated that transient and low-dose addition of the cancer drug bortezomib—a proteasome inhibitor currently used to treat B cell acute lymphoblastic leukemia—to CAR-T cell cultures during manufacturing reduces exhaustion-associated programs in the cells and maintains them in a proliferative and functionally vibrant state.
Proteasome-guided haem signalling axis contributes to T cell exhaustion
Nature, 2026 March 18