Mitochondrial-proteasome-heme axis rewires T cell fate and weakens cancer therapy

Cancer-fighting T cells do not simply "run out of energy." They are molecularly reprogrammed.

For years, mitochondrial dysfunction has been recognized as a hallmark of exhausted T cells in tumors. Yet how metabolic stress translates into stable transcriptional reprogramming remained unclear.

The new study uncovers a decisive molecular bridge.

When mitochondria become depolarized, CD8⁺ T cells increase proteasome activity. This heightened protein degradation selectively dismantles mitochondrial hemoproteins, releasing excess regulatory heme.

Rather than remaining a byproduct, heme becomes a signal.

It translocates to the nucleus, where it binds and destabilizes the transcription factor Bach2, relieving repression of Blimp1, a master regulator of terminal exhaustion. The collapse of the Bach2–Blimp1 axis locks T cells into a dysfunctional state and erodes their stem-like potential.

Mechanistically, the researchers identify CBLB as a driver of mitochondrial protein ubiquitination and PGRMC2 as a chaperone enabling nuclear heme transport.

A molecular switch and a therapeutic opportunity

"We uncovered a metabolic signaling switch that converts mitochondrial stress into a permanent transcriptional decision," says Professor Ping-Chih Ho, senior author of the study. "This pathway explains how energy failure becomes immune failure."

Crucially, the axis is actionable.

The team shows that transient low-dose bortezomib treatment during CAR-T cell manufacturing dampens proteasome-driven heme signaling, reduces exhaustion-associated programs, and promotes durable epigenetic reprogramming toward a memory-like state.

Clinical relevance is reinforced by data from B-ALL patients: CAR-T cells exhibiting high proteasome activity correlate with poorer therapeutic outcomes.

"Our last paper identified mitochondrial damage as the cause of T cell failure and this one reveals the molecular switch behind it, and how to turn exhaustion off. For a long time, mitochondrial dysfunction was an observation without a clear mechanistic explanation." says Y. Xu, first author of the study. "Discovering that regulatory heme acts as the signaling mediator was unexpected and it gives us a tangible way to intervene."

Reframing T cell exhaustion

The findings redefine T cell exhaustion not merely as a consequence of chronic antigen stimulation, but as the outcome of a dysregulated metabolic signaling circuit.

By identifying a proteasome-guided heme pathway that dictates immune cell fate, the study opens new strategies to optimize adoptive cellular immunotherapy, particularly CAR-T approaches, where durability remains a clinical challenge.

About the study:

The research was led by Y. Xu under the supervision of Professor Ping-Chih Ho, full professor at the Faculty of biology and medicine, at the University of Lausanne, in collaboration with institutions across Switzerland, China, Taiwan, the United Kingdom, and the United States.

The work was supported by the Swiss National Science Foundation, the Swiss Cancer Foundation, the Cancer Research Institute, the Helmut Horten Stiftung, the Melanoma Research Alliance, the National Key Research and Development Program of China, and multiple international funding bodies.