COLUMBUS, Ohio – In what experts are calling a paradigm-shifting landmark study, scientists from The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute (OSUCCC – James) report key findings about the underlying mechanisms of immune system stress response to protein misfolding, launching a new approach to cancer immunotherapy treatment targeting the protein production cycle.
For this study, OSUCCC – James researchers sought to answer a long-held question: Why do T cells, which are crucial for fighting infections and recognizing cancer, sometimes become "exhausted" and lose their effectiveness?
In this comprehensive preclinical study, researchers revealed a hidden vulnerability in exhausted T cells: they are overwhelmed by misfolded proteins that ignite a previously unrecognized stress pathway, now named TexPSR (proteotoxic stress response in T-cell exhaustion).
Unlike ordinary stress responses that slow protein production to help cells regain balance, TexPSR drives protein synthesis into overdrive. The result is a relentless buildup of misfolded proteins, stress granules, and toxic aggregates ¾ similar to the amyloid plaques seen in Alzheimer's disease. This overload poisons the T cells, crippling their ability to attack tumors.
Nature Reviews Immunology, a leading opinion journal in the field, described this phenomenon as a "proteotoxic shock." Strikingly, when researchers blocked key drivers of TexPSR in preclinical models, exhausted T cells recovered their function and cancer immunotherapy became markedly more effective.
"T-cell exhaustion is the biggest roadblock to cancer immunotherapy. Our study results present a surprising and exciting answer to this fundamental problem and could be critical to improving future scientific advances in the field of engineered cancer drug therapies to harness the immune system," said Zihai Li, MD, PhD , senior study author and founding director of the Pelotonia Institute for Immuno-oncology (PIIO) at the OSUCCC – James.
Li, who also serves as Deputy Director for Translational Research at the OSUCCC – James and holds the Klotz Memorial Chair in Cancer Research, has studied the link between protein folding and immunity for over three decades. He emphasized: "Researchers worldwide are tackling T-cell exhaustion through studying genetics, epigenetics, metabolism and others, but the role of protein quality control has been largely overlooked — until now."
The Ohio State cancer research team also found that high levels of TexPSR in T cells from cancer patients were linked to poor clinical responses to immunotherapy. This suggests that targeting TexPSR could be a new way to enhance cancer treatment in the clinics.
"When T cells become exhausted, they continue creating molecular weapons but then destroy the weapons before they can do their job," said Yi Wang, first author and doctoral student in Li's laboratory.
The team's findings reveal that this self-perpetuating cycle of protein stress is a central driver of T-cell exhaustion, ultimately disabling the function of these immune cells. Notably, the mechanism was validated in multiple preclinical and clinical cancer models — including lung, bladder, liver cancer, and leukemia — highlighting its broad relevance across diverse cancer types.
Li and colleagues report their findings in the latest issue of Nature . To learn more about the PIIO, visit cancer.osu.edu/PIIO .
