CD8⁺ T cells are the frontline soldiers of the body against cancer, but their prolonged exposure to tumor antigens often leads to an exhausted state. This state is marked by weakened function, increased expression of inhibitory receptors, and profound epigenetic and metabolic reprogramming. While a subset known as precursor exhausted T cells retains some stem-like qualities and can respond to immunotherapy, terminally exhausted T cells are largely refractory to treatment. Preventing or reversing the progression to terminal exhaustion remains a central challenge.
To provide a mechanistic answer, a team of researchers led by Dr. Li Guideng from the Suzhou Institute of Systems Medicine, China, in collaboration with Dr. Philip D. Greenberg's team at the Fred Hutchinson Cancer Center, USA, published two complementary papers. The first, titled "Chronic TCR Signaling-Driven Suppression of the FOXO1-KLHL6 Axis Promotes T Cell Exhaustion," was made available online on January 14, 2026, in the journal Immunity & Inflammation . The other, titled "The Ubiquitin Ligase KLHL6 Drives Resistance to CD8+ T Cell Dysfunction," was published in the journal Nature on January 14, 2026. They demonstrate that persistent T cell receptor (TCR) signaling, instead of sustaining activation, acts as a master switch by suppressing the transcription factor FOXO1. This suppression leads to the sustained downregulation of an E3 ubiquitin ligase, KLHL6, a previously unrecognized pivotal event in initiating the exhaustion program.
Through integrative analysis of T cell exhaustion data from viral infection and tumor models, the researchers first identified dysregulation in protein degradation pathways as reported in the study in Nature. A subsequent computational-guided CRISPR screen pinpointed KLHL6 as a key factor capable of simultaneously suppressing exhaustion and improving mitochondrial function. Mechanistically, KLHL6 was found to ubiquitinate and target two key proteins for degradation: TOX, a master transcription factor of exhaustion, and PGAM5, a regulator of mitochondrial dynamics. Under chronic stimulation, decreased KLHL6 levels allow TOX to accumulate—accelerating exhaustion—and cause PGAM5 buildup, which promotes excessive mitochondrial fragmentation (via Drp1) and metabolic dysfunction.
The companion study in Immunity & Inflammation solved the upstream puzzle: How does chronic TCR signaling turn off KLHL6? The team discovered that acute TCR signaling transiently suppresses KLHL6 via the PI3K-AKT pathway, which phosphorylates and inhibits FOXO1, a transcription factor that binds to the KLHL6 promoter. Critically, under persistent antigen stimulation, FOXO1 activity is chronically suppressed, leading to irreversible downregulation of KLHL6 and locking T cells into the exhaustion pathway.
The research further established the functional hierarchy within this axis. While FOXO1 is known to promote memory formation in CAR-T cells, the team found that KLHL6 overexpression could rescue the anti-tumor function and memory potential of FOXO1-deficient T cells. "This indicates that KLHL6 is a major downstream executor of FOXO1's beneficial effects on T cell fitness," the authors noted.
These findings establish the FOXO1-KLHL6 axis as a core regulator translating chronic antigen exposure into a state of T cell exhaustion. They offer a mechanistic explanation for a long-standing paradox in immunology and reveal KLHL6 as a highly promising therapeutic target. "Strategies to boost KLHL6 activity or mimic its function—such as developing protein degraders targeting TOX/PGAM5 or KLHL6 agonists—could potentially prevent or reverse T cell exhaustion, thereby enhancing the efficacy of existing immunotherapies like immune checkpoint blockade, CAR-T, and TCR-T cell therapies," the authors highlighted.
