University of Lausanne Researchers Identify Mitochondrial Metabolic Switch That Drives Immune Cell Exhaustion and Weakens Cancer Therapy

Researchers at the University of Lausanne find a mitochondrial signaling axis that causes T cell failure, offering a new way to improve CAR-T cancer therapy.

By: AXL Media

Published: Mar 18, 2026, 3:07 PM EDT

Source: Information for this report was sourced from University of Lausanne

Decoding the Molecular Reprogramming of T Cells

For years, scientists have observed that T cells fighting within tumors often "run out of energy," a state known as immune exhaustion marked by mitochondrial dysfunction. However, new research from the University of Lausanne has revealed that these cells are not merely exhausted; they are molecularly reprogrammed through a sophisticated metabolic signaling circuit. The study, published by the research group of Professor Ping-Chih Ho, identifies a decisive bridge between energy failure and immune failure. When mitochondria become stressed, they trigger a cascade that permanently locks T cells into a dysfunctional state, eroding their ability to effectively combat cancer over the long term.

The Discovery of the Heme Signaling Axis

The research team uncovered that when a T cell's mitochondria become depolarized, the cell responds by increasing proteasome activity—the internal machinery responsible for degrading proteins. This process selectively dismantles mitochondrial hemoproteins, which in turn releases an excess of regulatory heme into the cell. Rather than remaining a simple metabolic byproduct, this heme acts as a powerful signal that translocates to the cell's nucleus. Once there, the heme binds to and destabilizes the transcription factor Bach2. This molecular shift relieves the repression of Blimp1, a master regulator that essentially "locks" the T cell into a state of terminal exhaustion.

Identifying the Drivers of Immune Failure

Mechanistically, the study identified two key players in this destructive circuit: CBLB and PGRMC2. The researchers found that CBLB acts as a driver of mitochondrial protein ubiquitination, essentially "tagging" the proteins for destruction. Meanwhile, PGRMC2 serves as a chaperone, a specialized transport molecule that enables the excess heme to reach the nucleus. This pathway explains how a temporary state of energy failure is converted into a permanent transcriptional decision by the cell. Professor Ping-Chih Ho notes that for a long time, mitochondrial dysfunction was merely an observation; this study finally provides the clear mechanistic explanation for why it occurs.