A new study published on Mar. 18 reveals that T cells used to fight cancer are not simply depleted of energy, but instead undergo a molecular reprogramming process that affects their function. The research, led by Y. Xu under the supervision of Professor Ping-Chih Ho at the University of Lausanne, uncovers a previously unknown link between mitochondrial dysfunction and stable changes in gene expression within these immune cells.
This discovery is significant because it sheds light on why some cancer therapies, such as CAR-T cell treatments, lose effectiveness over time. Understanding the mechanisms behind T cell exhaustion could help improve the durability and success of immunotherapies for patients.
The researchers found that when mitochondria in CD8⁺ T cells become depolarized, there is an increase in proteasome activity. This leads to selective degradation of mitochondrial hemoproteins and the release of regulatory heme. The released heme then moves into the nucleus where it binds to and destabilizes the transcription factor Bach2, which normally represses Blimp1—a key regulator associated with terminal exhaustion. As a result, T cells become locked into a dysfunctional state and lose their stem-like qualities.
Professor Ping-Chih Ho said, "We uncovered a metabolic signaling switch that converts mitochondrial stress into a permanent transcriptional decision. This pathway explains how energy failure becomes immune failure." First author Y. Xu added, "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... Discovering that regulatory heme acts as the signaling mediator was unexpected and it gives us a tangible way to intervene."
The study also identifies CBLB as responsible for tagging mitochondrial proteins for degradation and PGRMC2 as aiding nuclear transport of heme. Importantly, experiments showed that using low-dose bortezomib during CAR-T cell manufacturing can reduce this proteasome-driven heme signaling and promote more durable memory-like states in these therapeutic cells.
Clinical data from B-ALL patients indicated that higher proteasome activity in CAR-T cells correlates with poorer outcomes. The findings suggest new strategies for optimizing adoptive cellular immunotherapy by targeting this newly discovered metabolic pathway.
