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Unraveling AMPK and BET regulation of immune checkpoint biology: implications for personalized medicine

Christina S Ennis, Kunlin Huang, Allison N Casey

    Biorxiv : the Preprint Server for Biology
    |February 9, 2026
    PubMed

    Insights

    Triple negative breast cancer (TNBC) patients with type 2 diabetes (T2D) have poorer outcomes. Bromodomain and ExtraTerminal domain (BET) proteins and 5' Adenosine Monophosphate-activated Protein Kinase (AMPK) influence immune checkpoints, potentially improving immunotherapy for TNBC with T2D.

    Area of Science:

    • Immunology
    • Oncology
    • Metabolic Disease

    Background:

    • Triple negative breast cancer (TNBC) patients with type 2 diabetes (T2D) exhibit worse survival rates.
    • The efficacy of immune checkpoint blockade (ICB) in TNBC is not well-defined.
    • Type 2 diabetes (T2D) is associated with immune suppression, and metformin's activation of 5' Adenosine Monophosphate-activated Protein Kinase (AMPK) warrants investigation into AMPK's role in immune checkpoint regulation.

    Purpose of the Study:

    • To investigate the role of AMPK and Bromodomain and ExtraTerminal domain (BET) proteins in regulating immune checkpoint expression in TNBC.
    • To explore potential therapeutic strategies for improving ICB efficacy in TNBC patients, particularly those with comorbid T2D.

    Main Methods:

    • Utilized flow cytometry to analyze immune checkpoint protein expression (TIM-3, TIGIT, PD-1, CTLA-4) on stimulated peripheral blood mononuclear cells.
    • Employed chemical inhibition of AMPK (Compound C) and BET proteins (pan-BET inhibitor JQ1, BRD4-selective PROTAC inhibitor MZ-1) to assess their regulatory pathways.

    Main Results:

    • BET proteins differentially regulate immune checkpoint proteins TIM-3, TIGIT, PD-1, and CTLA-4.
    • BET proteins regulate PD-1 and CTLA-4 via an AMPK-dependent pathway.
    • BET proteins regulate TIM-3 and TIGIT via an AMPK-independent pathway.

    Conclusions:

    • BET proteins and AMPK play distinct roles in regulating immune checkpoints relevant to TNBC.
    • Targeting BET proteins and AMPK pathways may offer personalized therapeutic strategies to enhance ICB efficacy in TNBC patients with T2D.

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