Therapeutic resistance to immune checkpoint blockade and adoptive cell therapy is driven in part by CD8+ T-cell exhaustion, yet the metabolic and molecular mechanisms enforcing terminal exhaustion remain incompletely defined. Xu and colleagues identify a mitochondrial stress–responsive proteasome–heme signaling axis that actively drives transcriptional reprogramming toward terminal exhaustion and limits antitumor T-cell durability. Through integrated single-cell transcriptomic, proteomic, and functional assays, exhausted CD8+ T cells were shown to selectively increase proteasome activity in response to the accumulation of depolarized mitochondria. Rather than inducing global protein turnover, the proteasome preferentially degraded mitochondrial proteins, including heme-containing respiratory chain components. This selective degradation resulted in elevated regulatory heme levels, which were shown to rise progressively with exhaustion severity in tumor-infiltrating lymphocytes and CAR T cells. Mechanistically, increased heme directly disrupted the transcriptional activity of BACH2, a key regulator of stemness in progenitor exhausted T cells. Heme binding promoted BACH2 degradation, derepressed BLIMP1, and reshaped chromatin accessibility to favor terminal exhaustion–associated transcriptional programs. Enforced heme exposure was sufficient to drive exhaustion phenotypes ex vivo and impair immune responses in vivo, whereas genetic ablation of BACH2 heme binding preserved progenitor exhausted states. Furthermore, nuclear transport of heme was required for these effects. Deletion of the heme chaperone PGRMC2 prevented nuclear heme accumulation, restored mitochondrial fitness, preserved BACH2 expression, and enhanced CD8+ T-cell effector function, tumor control, and survival in mouse models. These mechanisms extended to the context of adoptive immunotherapy, wherein high proteasome activity signatures in CD19 CAR T cells correlated with poor clinical outcomes in patients with B cell acute lymphoblastic leukemia. Transient proteasome inhibition during CAR T-cell manufacturing using low-dose bortezomib reduced exhaustion, induced durable epigenetic reprogramming toward memory-like states, and markedly improved antitumor efficacy in vivo. Together, these findings define a mitochondrial integrity–sensing pathway in which proteasome-guided heme signaling enforces T-cell exhaustion and identifies actionable strategies to enhance cellular immunotherapy.Xu Y, Shangguan Y, Chuang Y-M, Chang T-H, Liu W, Peng J-J, et al. Proteasome-guided haem signalling axis contributes to T cell exhaustion. Nature 2026 Mar 18 Epub ahead of print.Note: Research Watch is written by Cancer Discovery editorial staff. Readers are encouraged to consult the original articles for full details. For more Research Watch, visit Cancer Discovery online at https://aacrjournals.org/cdnews.
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