HMN 2026: How T cells gain superior memory through new reprogramming method, boosting cancer-fighting abilities

Georgetown University’s Lombardi Comprehensive Cancer Center researchers have identified a new way to reprogram T cells, which are infection and tumor-fighting white blood cells, so that they have a superior memory, thereby making them more effective in killing cancer cells.

The finding, published January 12, 2026, in Nature Immunology, amplifies a known strategy of blocking the cellular activity of PARP, an enzyme that detects DNA abnormalities in cells and repairs them.

“This opens the door to a new area of research in understanding how our immune system works, and as importantly, it opens the way for the development of new strategies for the treatment of cancer,” says Samir N. Khleif, MD, director of The Center for Advanced Immunotherapy Research and the director of Loop Immuno-Oncology Research Laboratory at Georgetown’s Lombardi.

How PARP inhibitors enhance T cells

When PARP functions in overdrive it helps fuel cancer growth and drugs used to block PARP are called PARP inhibitors. Georgetown researchers found that inhibiting PARP with such drugs in a key group of immune cells, called CD8 T cells, can significantly enhance the function of these cells and boost the body’s immune response against tumors.

In their in vitro and mouse studies, the researchers determined that PARP inhibition helps CD8 T cells develop into a superior memory form, that they become activated more effectively, and that they attack cancer cells more forcefully. This process is achieved by reprogramming the cells’ metabolism, making them stronger and longer lasting in the fight against cancer. In essence, these enhanced memory T cells show better recall and anti-tumor activity.

PARP inhibitors can be effective in treating several cancers that carry specific mutations, such as BRCA mutations, that lead to defects in DNA repair. Importantly, in this new finding, the investigators identified a role for these drugs in enhancing the anti-tumor immune effect regardless of the presence of specific DNA mutations in the cancer.

Expanding the potential of immunotherapy

According to Khleif, this finding expands the potential use of PARP inhibitors into many types of cancer and suggests that PARP inhibitors can be used in combination with immunotherapy to widen their utility and potentially achieve higher efficacy.

“The new T cells that we identified are superior memory T cells. They exhibit a stronger response to foreign antigens and possess prolonged survival, leading to greater and more robust anti-tumor activity. They are crucial for strong, long-lasting anti-tumor immune responses, which can be linked to better patient outcomes,” notes Khleif. “By promoting these T cells, PARP inhibitors could potentially make cancer immunotherapy more effective.”

In previous research published in Nature Immunology, Khleif and his team discovered another T cell reprogramming strategy by targeting a pathway different than the PARP pathway. They found that the MEK pathway could be also used in different settings for enhancing cancer therapy.

“Together, our two recent studies pave the way for a new and important field of investigation, which is targeting signaling pathways by using small molecules for reprogramming T cells into novel and specific subtypes,” says Khleif.

Next steps and clinical implications

Small molecule inhibitors, such as olaparib, which is one of the drugs that the investigators used in their experiments, and which is currently used to treat people with certain forms of cancer, can easily enter cells, unlike large antibodies, to hit intracellular pathway targets. The effects of such inhibitors can be precisely tuned or reversed by changing their concentrations and they are also easy to administer as they can be delivered orally.

For their next step, the scientists hope to translate this discovery into strategies that could be tested in clinical trials to treat patients with difficult-to-treat cancers.

For example, there are currently no clinical trials combining PARP inhibitors with ACT (adoptive cell therapy) or CAR (chimeric antigen receptor)-T cell therapies, which are personalized types of immunotherapies.

Khleif and his colleagues are exploring the possibility of developing such a clinical trial for patients with ovarian, breast or prostate cancers using these combination therapies.

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