Proteasome-guided haem signalling axis contributes to T cell exhaustion
Article metadata
Article Date: 18 March 2026
Article URL: https://www.nature.com/articles/s41586-026-10250-y
Article Image: (not provided)
Summary
This Nature paper identifies a proteasome-driven mechanism that promotes terminal exhaustion in CD8+ T cells. The authors show that increased proteasome activity in exhausted T cells drives degradation of mitochondrial proteins, which releases regulatory haem. That haem is transported into the nucleus (via a haem chaperone such as PGRMC2) and reprogrammes transcription through the BACH2–BLIMP1 axis, pushing T cells towards terminal, dysfunctional states.
The study combines proteomics, bulk and single-cell RNA-seq, ATAC-seq and functional assays in mouse tumour models and human CAR‑T samples. Genetic and pharmacological interventions that reduce proteasome activity or block haem nuclear translocation (for example Pgrmc2 conditional knockout, or low-dose bortezomib pretreatment) preserve T cell effector functions and improve antitumour activity of CAR‑T cells in preclinical models.
Datasets (bulk RNA-seq, ATAC-seq, scRNA-seq and single-cell multi-omics) from mouse and human samples are publicly available under multiple accession numbers (see article). The paper presents extensive extended-data figures supporting the proteasome–haem–BACH2/BLIMP1 signalling axis and translational implications for improving CAR‑T durability.
Key Points
- Terminally exhausted CD8+ T cells show elevated proteasome activity that selectively degrades mitochondrial proteins.
- Mitochondrial protein degradation releases regulatory haem which translocates to the nucleus and alters transcription.
- Haem signalling represses BACH2 and induces BLIMP1, driving terminal differentiation and loss of T cell function.
- Blocking haem nuclear import (Pgrmc2 loss) or modulating proteasome activity (low‑dose bortezomib) sustains effector function and improves CAR‑T performance in preclinical models.
- Multimodal data (proteomics, scRNA-seq, ATAC-seq) from human CAR‑T cells and mouse tumours corroborate the mechanism and suggest immediate translational entry points.
Why should I read this
Short version: if you care about why CAR‑T and tumour‑infiltrating CD8+ cells burn out, this paper nails down a biochemical route — proteasome eats mitochondrial proteins, haem gets loose, and that flips a transcriptional switch that kills T cell stamina. The authors back it with human CAR‑T data and show ways to block it. Read it if you want clever, potentially druggable fixes to make T cells last longer.
Author style
Punchy: the team links a clear biochemical chain (proteasome → mitochondrial protein loss → haem release → nuclear signalling → BACH2/BLIMP1-driven exhaustion) to functional outcomes and therapeutic tests. This is highly relevant for anyone working on T cell metabolism, exhaustion or improving adoptive cell therapies — it points to concrete interventions rather than abstract pathways.
Context and relevance
T cell exhaustion limits the success of immunotherapy and adoptive cell therapy. This study sits at the intersection of proteostasis, mitochondrial health and nuclear transcriptional control, adding haem as a central signalling mediator. The work connects metabolic stressors in the tumour microenvironment to durable transcriptional remodelling of T cells and suggests repurposing or optimising proteasome inhibitors and haem‑transport blockers to enhance CAR‑T efficacy. It therefore advances both basic understanding and translational strategy in cancer immunotherapy.