New Insights on PD-1: Role in Skin Immunity and Cancer Treatment

Researchers at Weill Cornell Medicine have unveiled a groundbreaking discovery regarding PD-1, a molecule traditionally recognized for its role in inhibiting immune cells. In a study published on July 29, 2025, in *Nature Immunology*, scientists revealed that PD-1 is also crucial in converting T cells into long-term immune defenders in the skin, a finding that could reshape approaches to cancer immunotherapy.

The research team, led by Dr. Niroshana Anandasabapathy, an associate professor of dermatology and microbiology/immunology at Weill Cornell Medicine, found that PD-1 functions like a steering wheel during early infection stages, guiding T cells to become protective resident memory T cells (TRM). These TRM cells remain in the skin and can provide rapid defense against previously encountered pathogens or cancer cells.

This discovery challenges the prevailing notion that PD-1 solely suppresses immune responses. "We observed that PD-1 is required for memory T cells to develop and anchor in skin, putting them in the right spot to have a role in side effects," Dr. Anandasabapathy stated. The implications of this finding are significant, particularly for the use of immune checkpoint inhibitors in cancer treatments, which target PD-1 to unleash the immune system against tumors. While effective for conditions such as melanoma, these therapies can cause inflammatory side effects in about 40% of patients, leading to rashes and discomfort.

The study utilized a combination of genetic modifications and pharmacological interventions in mice. The researchers blocked PD-1 to assess its role in T cell memory formation. Their results indicated that without PD-1, T cells were unable to establish memory or anchor themselves in the skin shortly after infection. "We showed genetically, pharmacologically, and with imaging that you need PD-1 to form resident memory T cells," Dr. Anandasabapathy explained.

Moreover, the research identified the cytokine TGF-β as a possible player in this memory-forming process. The researchers noted that TGF-β signaling is required for the formation of TRM cells in certain locations, such as the skin and lungs. However, when PD-1 was inhibited too early during the immune response, TRM cell formation was compromised, potentially leading to adverse side effects in patients undergoing cancer treatments.

The findings suggest that modifying the timing of PD-1 blockade in immunotherapy could minimize these undesirable effects. "These results could guide the development of better therapies targeting PD-1 without unwanted side effects for cancer patients," remarked Sanjana P. Devi, one of the study's first authors, who is now at Quest Diagnostics.

This research not only provides insights into cancer treatment but also has implications for autoimmune therapies. "Some strategies block PD-1 very early, which may unintentionally disrupt TRM cell formation—we need to think about blocking PD-1 in the right context and in a timed way," Dr. Anandasabapathy added.

The study's findings could herald a new era in the treatment of cancer and autoimmune diseases, highlighting the necessity of understanding the dual roles of immune molecules like PD-1. As researchers continue to investigate the intricate dynamics of the immune system, the potential for developing more effective and less harmful therapies grows ever more promising.