This research identifies a novel biological pathway where mitochondrial dysfunction triggers T cell exhaustion, a state of reduced effectiveness that hinders the body's ability to fight cancer. Scientists discovered that when mitochondria lose their integrity, cells increase proteasome activity to degrade damaged proteins, an action that inadvertently releases regulatory haem. This excess haem enters the nucleus and disrupts BACH2, a critical transcription factor responsible for maintaining the "stem-like" regenerative capacity of immune cells. The study demonstrates that high proteasome gene signatures in patients receiving CAR-T cell therapy correlate with poor clinical outcomes and rapid cancer relapse. To combat this, researchers found that using bortezomib, a proteasome inhibitor, during the manufacturing of CAR-T cells prevents exhaustion and significantly boosts their anti-tumour efficacy. These findings suggest that targeting the proteasome-haem axis offers a promising strategy to enhance the durability and success of adoptive cellular immunotherapies.

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