Fasting-Induced Histone Changes Restore T Cell Function Against Liver Cancer

A study in Theranostics has revealed how short-term fasting can reprogram exhausted immune cells to better combat liver cancer. The findings highlight the critical role of histone modifications—key epigenetic regulators of gene activity—in restoring immune function, and point to new strategies that combine metabolic interventions with cancer immunotherapy.

Linking Fasting to Epigenetic Regulation

When faced with chronic tumors such as liver cancer, T cells—the immune system’s frontline defenders—often enter a state of “exhaustion,” limiting their effectiveness. While researchers have long studied the signaling pathways that drive this dysfunction, the epigenetic mechanisms behind T cell rejuvenation have remained less understood.

Histones, the protein spools around which DNA is wrapped, carry chemical modifications that act as on/off switches for genes. These modifications can profoundly affect how immune cells behave, determining whether they remain in a fatigued state or regain the ability to proliferate and attack.

Inside the Study

To uncover the connection between fasting and histone regulation, researchers induced short-term fasting in a liver cancer model and tracked the effects on T cells. They found that fasting disrupted signaling through the CD36 protein, activating downstream pathways that ultimately led to the breakdown of RBPJ, a transcription factor that promotes T cell exhaustion. Without RBPJ, T cells showed enhanced activity and responsiveness to tumors.

To measure the chromatin-level changes accompanying this shift, the team used EpigenTek’s EpiQuik™ Histone H3 Modification Multiplex Assay Kit. This unique platform allowed simultaneous detection of 22 different histone H3 modifications from T cells. The analysis revealed a broad increase in histone activation marks, with H3S10 phosphorylation (H3S10P) showing the most dramatic elevation. This histone change is strongly linked to gene activation and cell proliferation, directly connecting fasting to a more potent immune response.