Zihai Li

Zihai Li is an American Board of Internal Medicine-certified/eligible medical oncologist, cancer immunologist, and leader in academic medicine. He was recruited to Ohio State University Comprehensive Cancer Center – The James Cancer Hospital & Solove Research Institute (OSUCCC) in 2019 as the founding director of the Pelotonia Institute for Immuno-Oncology. He is a professor of medicine in the Division of Medical Oncology, holds the Klotz Memorial Chair for Cancer Research, and was appointed in 2023 as deputy director for translational research at OSUCCC.

Li's research interests primarily focus on the fields of proteostasis, chaperone biology, immune tolerance, cancer immunology and immunotherapy. He has been continuously funded by the National Institutes of Health (NIH) since 2000, with total funding of over $30 million.

Career Following his residency and fellowship, Li began his first joint faculty appointment in the Department of Immunology and Medicine at the University of Connecticut School of Medicine (Farmington, CT). In 2010, he was recruited to the Department of Microbiology and Immunology at the Medical University of South Carolina (MUSC), where he served as chair from 2010-2019. During his tenure as chair, the department doubled its NIH funding and increased its national NIH ranking from 79 to 31. Li was also appointed the leader of the Cancer Immunology Program at MUSC's Hollings Cancer Center (2010-2019). Li was inducted into the American Society of Clinical Investigation (2009) and the Association of American Physicians (2018) and is an elected fellow of the American Association for the Advancement of Science (2021) for his work in the interface of chaperone biology and cancer immunology. Recognizing his history of mentorship, he was awarded the Peggy Schachte Research Mentor Award in 2016 from MUSC. In 2022, he received the Mount Sinai Alumni Award for Achievement in Graduate Education.

Contributions to science Chaperone biology and immune regulation

Li has made groundbreaking discoveries studying the immune chaperone gp96 (also called GRP94), an endoplasmic reticulum-resident protein chaperon belonging to the HSP90 family of heat shock proteins. His research revealed that gp96 is pivotal in various physiological processes, including organ development, innate immunity, and immune tolerance. In cancer, gp96 expression is not only abundant but also further upregulated, driving oncogenesis through its growing client network.

Background: In the 1950s, Prehn, Main, Klein, Old, and others demonstrated the existence of protective immunity against cancer in mice using syngeneic tumor models. This was followed by decades of effort to identify tumor rejection antigens. Pramod Srivastava and Lloyd J. Old isolated a ubiquitous conserved protein, gp96, as a tumor rejection antigen from several chemically induced fibrosarcoma models.

Major contribution to gp96/GRP94 biology: Li defined the ATPase activity of gp96/GRP94, its client network, and the co-chaperone CNPY3. However, there were no previous publications regarding the function of gp96/GRP94 when Li began to study this molecule in the 1990s. It remained unclear how this unmutated protein could trigger an immune response in animals against the tumor from which it originated. Through a biochemical approach, Li was the first to demonstrate that gp96/GRP94 is a bona fide member of the HSP90 family, exhibiting ATP binding, intrinsic ATPase activity, and peptide chaperoning functions. Li was the first to use mammalian genetics to uncover the function of GRP94 at the organismal level. He discovered that GRP94 is a major chaperone for integrins, Toll-like receptors (TLRs), the platelet receptor for the von Willebrand factor, and the latent TGFβ docking receptor GARP

Li’s team discovered that exhausted T cells accumulate misfolded proteins that trigger a unique stress response termed the T-cell exhaustion–associated proteotoxic stress response (TexPSR). In addition, he contributed to the first report that loss of the Y chromosome in tumor cells causes T cell dysfunction and increased sensitivity to anti-PD-1 immunotherapy. Li's work has been fundamental in establishing the immunological basis of sex bias in cancer.

Li's other contributions to the field of medicine and biology include the discovery of a molecular key from platelets (via GARP) for cancer immune evasion and the first demonstration of CNPY2 as a critical sensor for PERK-mediated unfolded protein response.