Since its discovery in the early 1990s, programmed cell death protein 1 (PD-1) has become a pivotal target in cancer research. A checkpoint receptor found on immune system cells, particularly T cells, PD-1 plays a crucial role in maintaining immune tolerance. Under normal circumstances, PD-1 functions as a sort of “off switch” to regulate immune responses, preventing the immune system from attacking normal cells in the body. This regulatory action ensures that immune cells do not damage the body’s own tissues, thereby avoiding autoimmune diseases.
However, cancer cells have discovered a way to exploit this regulatory mechanism. Tumor cells often express proteins that activate PD-1, effectively shutting down the immune response that could otherwise target and destroy the cancerous cells. This creates a shield of sorts, allowing the cancer cells to evade immune surveillance and continue growing undisturbed. Recognizing the therapeutic potential of blocking this “off switch,” researchers began developing PD-1 inhibitors that can reactivate the immune system, allowing it to recognize and fight cancer cells.
The success of PD-1 inhibitors in treating cancers such as melanoma, lung cancer, and other solid tumors was groundbreaking, earning the developers the Nobel Prize in Physiology or Medicine in 2018. These immunotherapy drugs, such as pembrolizumab (Keytruda) and nivolumab (Opdivo), have marked a new era in cancer treatment, demonstrating impressive clinical efficacy in some patients and dramatically changing the therapeutic landscape.
Despite the initial excitement, however, there is an important limitation. PD-1 blockade treatments do not work for all cancer patients. In fact, only a subset of patients respond positively to PD-1 inhibitors, suggesting that there are still many unknowns about the exact functioning of PD-1 and its interactions with the immune system. To address this gap, scientists have long relied on preclinical models, primarily involving mice, under the assumption that the PD-1 molecule functions similarly across species. Mice, being mammals with immune systems analogous to human systems, have been the gold standard for testing cancer therapies. However, new research is now challenging this assumption, showing that the human PD-1 receptor significantly differs from its mouse counterpart.
Recent studies conducted by scientists from UC San Diego’s School of Biological Sciences, in collaboration with researchers at the Chinese Academy of Sciences, have identified a critical discrepancy between mouse and human PD-1. Their work, published in Science Immunology, offers a detailed examination of PD-1 across species and brings to light unexpected differences that could have profound implications for developing better models for preclinical testing and ultimately more effective treatments.
The study, led by assistant project scientist Takeya Masubuchi, reveals that PD-1 in mice is much weaker than the human version. This insight stems from their discovery of a distinct sequence of amino acids—an important motif—that is present in most mammals, including humans, but surprisingly absent in rodents. This motif’s absence in mice makes their PD-1 receptor less effective in regulating immune activity. “Our work uncovers unexpected species-specific features of PD-1,” explained Associate Professor Enfu Hui, one of the senior authors. “We found that this motif, which is present in most mammals, including humans, is missing in rodents, making mouse PD-1 distinctly weaker.”
This difference in the structure of PD-1 has significant implications for the effectiveness of cancer immunotherapies. Mouse models, commonly used in preclinical research, may not provide an accurate representation of how PD-1 inhibitors would behave in human patients. As a result, testing cancer drugs in mice might not translate as effectively to humans, thereby skewing the results of preclinical trials.
Further investigation into the humanization of PD-1 in mice showed an even more surprising finding. By replacing mouse PD-1 with the human version, researchers observed that the immune cells, particularly T cells, were less able to combat tumors. This reversal of immune function after humanizing the mouse PD-1 suggests that the differences between species are not just structural, but functional as well.
“Our study shows that as science progresses, we must have a deep, nuanced understanding of the models we use to develop new medicines and treatments,” remarked Professor Jack Bui, co-senior author of the paper. “Finding that rodents might be outliers in terms of PD-1 activity forces us to rethink how to deploy medicines to human patients. If we’ve been using rodent models for drug testing, but rodents have significantly weaker PD-1 activity, it calls for the consideration of better model systems, ones that more closely resemble human immunology.”
To explore the evolutionary origins of this divergence, the research team also traced the PD-1 receptor’s evolutionary history, investigating how it might have changed over millions of years. Collaborating with Professor Zhengting Zou from the Chinese Academy of Sciences, the researchers used an evolutionary approach to identify a significant shift in PD-1 activity about 66 million years ago, following the Cretaceous–Paleogene (K–Pg) mass extinction event. This event wiped out the non-avian dinosaurs and altered the evolutionary path of surviving species.
Interestingly, their analysis revealed that the PD-1 receptor in rodents, compared to other vertebrates, is uniquely weakened. This weakening of PD-1 might be a result of specific adaptations in rodents to environmental pressures and the presence of unique rodent-specific pathogens. It is possible that rodents evolved a less robust PD-1 response to cope with their environment, potentially making them more resilient to certain diseases but less able to combat tumors effectively. “The rodent ancestors survived the extinction event, but their immune receptor activities might have been altered as a consequence of adaptation to new ecological challenges,” Hui noted.
The researchers’ findings suggest that this alteration in PD-1 activity may offer insight into why certain cancer immunotherapies that target PD-1 may be less effective in rodent models, and how species differences can influence disease outcomes. This also raises the important point that not all immune system regulators function the same way across species, emphasizing the need for human-specific models in immunology and cancer research.
The implications of this study are far-reaching. As cancer treatments continue to evolve, a deeper understanding of PD-1’s behavior in humans compared to animals like mice will be essential. Researchers will likely need to develop more accurate humanized animal models or even explore alternative approaches such as organoid systems, which can simulate human tissue more closely than animal models.
Future studies will focus on examining how these insights into PD-1 may influence the development of treatments targeting tumors across various types of cancer. Researchers are also exploring the potential of incorporating human PD-1 characteristics into drug testing protocols to enhance the predictive power of preclinical studies and improve the translation of therapeutic interventions from animal models to human patients.
Reference: Functional differences between rodent and human PD-1 linked to evolutionary divergence, Science Immunology (2025). DOI: 10.1126/sciimmunol.ads6295