Related Experiment Video

Updated: Jul 18, 2025

Generation of Prostate Cancer Cell Models of Resistance to the Anti-mitotic Agent Docetaxel
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Published on: September 8, 2017

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Overcome Prostate Cancer Resistance to Immune Checkpoint Therapy with Ketogenic Diet-Induced Epigenetic Reprogramming

Sean Murphy, Sharif Rahmy, Dailin Gan

    Biorxiv : the Preprint Server for Biology
    |August 23, 2023
    PubMed

    Insights

    Advanced prostate cancer (PCa) is resistant to immune checkpoint blockade (ICB) therapy. Combining ICB with HDAC inhibitors or ketogenic diets enhances anti-tumor immunity and efficacy in a preclinical PCa model.

    Area of Science:

    • Oncology
    • Immunology
    • Metabolic pathways

    Background:

    • Advanced prostate cancer (PCa) exhibits significant resistance to immune checkpoint blockade (ICB) therapy.
    • Developing strategies to overcome ICB resistance in PCa is a critical clinical need.

    Approach:

    • A syngeneic murine PCa model with acquired ICB resistance was utilized.
    • Synergistic efficacy was investigated by combining ICB (anti-PD1 and anti-CTLA4) with histone deacetylase inhibitor (HDACi) vorinostat, a cyclic ketogenic diet (CKD), or β-hydroxybutyrate (BHB) supplementation.
    • Mechanisms were elucidated using single-cell transcriptomic and proteomic profiling.

    Key Points:

    • Both CKD and BHB supplementation demonstrated monotherapy efficacy in delaying PCa tumor growth.
    • BHB and adaptive immunity were identified as crucial for the anti-tumor activity of CKD.
    • HDACi and ketogenesis-enhanced ICB therapy modulated cancer-cell-intrinsic (MHC class I upregulation) and extrinsic mechanisms (immune cell recruitment and rebalancing).

    Conclusions:

    • HDAC inhibitors and optimized ketogenic diets show potential for enhancing ICB therapy in prostate cancer.
    • The combination strategies induced favorable immune microenvironment changes, including CD8+ T cell attraction and altered myeloid cell populations.
    • These findings support the clinical investigation of combining HDACi and ketogenic strategies with ICB for advanced PCa.

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