T Cell Exhaustion Mechanisms in Myeloid Malignancies

In myeloid malignancies, including acute myeloid leukaemia and related disorders, persistent antigen exposure drives CD8+ and CD4+ T cells into a hypofunctional state termed exhaustion. Chronically stimulated T cells gradually upregulate inhibitory receptors such as PD-1, TIM-3 and TIGIT, while losing proliferative capacity, cytokine production and cytotoxicity. Underlying transcriptional programmes—most notably those governed by the TOX family of HMG-box transcription factors—establish and stabilise the exhausted phenotype through widespread epigenetic remodelling. Metabolic dysregulation, characterised by impaired mitochondrial function and nutrient deprivation in the malignant bone marrow niche, further entrenches T cell hyporesponsiveness. In addition, immunosuppressive stromal elements and myeloid-derived suppressor cells secrete factors such as TGF-β and arginase, which reinforce exhaustion by dampening TCR signalling. Collectively, these mechanisms not only undermine anti-leukaemic immunity but also limit the efficacy of checkpoint blockade and adoptive T cell therapies. Understanding the molecular interplay between transcriptional regulators, metabolic cues and the tumour microenvironment has revealed new strategies to reinvigorate exhausted T cells and improve clinical outcomes in patients with myeloid malignancies.

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T Cell Exhaustion Mechanisms in Myeloid Malignancies publication trend

The graph below shows the total number of articles in t cell exhaustion mechanisms in myeloid malignancies across all publications each year (not limited to Nature Index journals).

Technical terms

T cell exhaustion: A hypofunctional state of chronic antigen-exposed T cells marked by high inhibitory receptor expression and diminished effector function.

Myeloid malignancies: Cancers arising from myeloid lineage precursors, including acute myeloid leukaemia, characterised by aberrant proliferation of immature myeloid cells.

Immune checkpoint: A regulatory pathway (e.g. PD-1/PD-L1, CTLA-4) that modulates T cell activation to maintain self-tolerance but can be exploited by tumours to evade immunity.

TOX (thymocyte selection-associated HMG box): A family of transcription factors that orchestrate epigenetic and transcriptional programmes underlying T cell exhaustion.

Tumour microenvironment: The local cellular and molecular milieu within the bone marrow or tumour site, including stromal cells, suppressive myeloid cells and soluble factors that shape immune responses.

References

1. Single-cell transcriptome analysis reveals TOX as a promoting factor for T cell exhaustion and a predictor for anti-PD-1 responses in human cancer. Genome Medicine (2020).
2. Memory T cells skew toward terminal differentiation in the CD8+ T cell population in patients with acute myeloid leukemia. Journal of Hematology & Oncology (2018).
3. Higher TOX Genes Expression Is Associated With Poor Overall Survival for Patients With Acute Myeloid Leukemia. Frontiers in Oncology (2021).