Stopping DNA damage in T cells during PARP inhibitor cancer treatment enhances antitumor effectiveness

The cancer drugs called PARP inhibitors have a puzzling reputation: even though they are treatment mainstays for multiple forms of cancer, they can damage cancer-killing T cells and disrupt the potential for meaningful therapy. New research from medical scientists in China is revealing ways to sidestep this obstacle by preventing PARP-induced collateral damage to T cells.

A multi-disciplinary team of researchers in Wuhan, working at several collaborating institutions, developed methods to prevent damage and showed that doing so increases the drugs’ efficacy against ovarian tumors and may help expand PARP inhibitors’ overall use. The PARP inhibitor drug family consists of slightly more than half a dozen medications, and the same problems appear consistent in all of them, say investigators participating in the study at Tongji Hospital, Tongji Medical College and Huazhong University of Science and Technology.

Writing in the journal Science Translational Medicinethe Wuhan-based researchers explain that PARP inhibitors have become standard treatments for epithelial ovarian cancerthe most lethal gynecologic cancer. However, PARP inhibitors often can’t eliminate tumors on their own. Doctors have attempted to combine PARP medication with immunotherapies, such as immune checkpoint inhibitorsbut results have been mixed, creating yet another obstacle in the PARP treatment saga.

“Seven orally administered PARP inhibitors have received global approval for the treatment of ovarian, breast, prostate, and pancreatic cancers, with others under development,” writes Dr. Jiahao Liu, lead author of the study.

Liu, a researcher in the department of gynecologic oncology at Tongji Hospital, noted that PARP inhibitors were developed with a very specific mode of action in mind: zeroing in on DNA—tumor DNA. A critical problem has been the medications’ capacity to damage the DNA of cancer-fighting T cells.

Poly (ADP-ribose) polymerase—PARP—inhibitors were actually designed to boost T cell activity to improve antitumor immunity. In other words, to coax T cells into a fight against the malignancy. Indeed, the inhibitors work against cancer cells by impairing the tumor’s ability to repair its DNA damaged by the treatment. A second prong of attack is coaxing T cells to wage war.

But the results of treating patients with PARP inhibitors have sometimes proved disappointing, even though PARP inhibitors have become routinely used not only in the treatment of ovarian cancer, but for several other tumor types. T cell loss is prevalent across all forms of cancer treated with a PARP inhibitor, Liu and colleagues report.

And there is yet another problem: Despite the drugs’ widespread usage, the Wuhan team found that PARP inhibitors often can’t eliminate tumors without the aid of additional anticancer medication.

“We found that patients’ T cells sustain DNA damage during PARP inhibitor treatment, which reduces treatment efficacy,” Liu added, noting the treatment not only caused DNA damage in T cells, but additionally slowed T cell proliferation and increased apoptosis in T cells. The team validated T cell DNA damage in mouse models and samples involving human tissue.

Regarding the human samples studied in the research, Liu and colleagues examined pre- and post-treatment specimens from patients with epithelial ovarian cancer. Post-treatment tests revealed that the PARP compounds damaged the DNA of patients’ T cells and slowed the cells’ proliferation, which forced T cells onto a path that ended in programmed cell death.

Using CRISPR, Liu and the team of researchers observed that PARP inhibitors damaged T cells through a mechanism involving the enzyme PARP1. Deleting PARP1’s gene in T cells or mutating the protein’s binding sites mitigated DNA damage and boosted the efficacy of PARP inhibitors in mice, either alone or in combination with the immune checkpoint inhibitor olaparib.

The Wuhan team also engineered CAR T cells that could tolerate PARP inhibitors and saw that these cells destroyed epithelial ovarian tumors more effectively than standard CAR T cells. In their mouse studies, Liu and the team of investigators found that decreasing PARP1 trapping tended to reduce DNA damage and improve tumor responses to a combination of PARP inhibitors.

The study, nevertheless, pointed to a paradox that was both puzzling and intriguing. While PARP inhibitors often result in incomplete tumor elimination, which can lead to treatment failure, the compounds have also been shown to enhance T cell-mediated antitumor immune responses, which may create an opportunity to continuously eliminate residual cancer cells.

“This study highlights the relevance of PARP [inhibitor]-induced DNA damage to T cells and suggests opportunities to improve the efficacy of PARP [inhibitors] as monotherapy or in combination with immunotherapy,” Liu and colleagues concluded.

© 2025 Science X Network