Re-Energizing T Cells May Help Patients Better Fight Cancer

Van Andel Institute scientists and collaborators have discovered a potential treatment target that may re-energize dysfunctional or “exhausted” immune cells in their fight against cancer.

The target is an immune checkpoint called PTGIR, which regulates the number and cancer-fighting powers of T cells, the soldiers of the immune system. Too much PTGIR puts a brake on T cells and reduces their ability to release cancer-killing molecules.

The findings, published in the journal Nature Immunology, could help improve cancer immunotherapies by paving the way for new immune checkpoint inhibitors or engineered T cell therapies that block PTGIR signaling and re-invigorate T cells.

“Immunotherapies are game changers for cancer treatment, but they don’t work for everyone or for all cancers,” said Michael Dahabieh, Ph.D., the study’s first author and a postdoctoral fellow in the lab of Russell Jones, Ph.D., at VAI. “Blocking PTGIR offers another opportunity to develop more targeted treatments that help the immune system fight disease.”

Immune checkpoints are molecules that pepper the outside of T cells and some cancer cells. In immune cells, checkpoints help the immune system do its job without accidentally attacking healthy cells. In cancer, checkpoints allow malignant cells to evade immune attacks. Medications that block checkpoints, called immune checkpoint inhibitors, have become powerful tools for treating cancer.

Most known immune checkpoints rely on interactions between proteins, which can limit treatment options. The new checkpoint is based on a protein (PTGIR) and a lipid (prostacyclin), which creates new prospects for leveraging the checkpoint to fight cancer. To date, only a few similar protein-lipid interactions have been described in T cells.

Prostacyclin is found in and around tumors and contributes to T cell exhaustion by interacting with PTGIR. The amount and availability of PTGIR is regulated by another protein called NRF2. More NRF2 means more PTGIR — which results in widespread T cell exhaustion.

“The more PTGIR, the more opportunities there are for it to interact with prostacyclin,” Jones said. “This increased activity slams the brakes on T cell activity and makes it more difficult for them to continue fighting cancer cells. Shutting down this interaction offers an opportunity to bolster the immune system and treat cancer.”

Reference: Dahabieh MS, DeCamp LM, Oswald BM, et al. The prostacyclin receptor PTGIR is a NRF2-dependent regulator of CD8+ T cell exhaustion. Nat Immunol. 2025. doi: 10.1038/s41590-025-02185-9

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