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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.
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.
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
Zihai Li, MD, PhD, senior study author and founding director of the Pelotonia Institute for Immuno-oncology (PIIO) at the OSUCCC – James.
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.
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.
(Newswise/ SP)
