Scientists just cracked the mystery of why cancer immunotherapy fails

Why Immune Cells Lose Their Power

The OSUCCC -- James research team set out to solve a long-standing puzzle in cancer biology: why do T cells, which are essential for attacking infections and recognizing tumors, sometimes wear out and lose their effectiveness?

Through extensive preclinical research, the scientists identified a hidden weakness in these "exhausted" T cells. They discovered that the cells are flooded with misfolded proteins, triggering a newly identified stress pathway called TexPSR (proteotoxic stress response in T-cell exhaustion).

Unlike typical cellular stress responses that slow protein production to restore balance, TexPSR has the opposite effect. It accelerates protein synthesis, leading to a buildup of misfolded proteins, toxic clumps, and stress granules -- similar to the amyloid plaques seen in Alzheimer's disease. This toxic overload effectively poisons the T cells, stripping them of their ability to destroy cancer cells.

Nature Reviews Immunology described this reaction as a "proteotoxic shock." Remarkably, when researchers blocked key elements of the TexPSR pathway in preclinical models, the exhausted T cells regained their strength, and immunotherapy became significantly more effective.

Restoring the Immune System's Strength

"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 OSUCCC -- James and holds the Klotz Memorial Chair in Cancer Research, has spent more than 30 years investigating how protein folding influences immune function. 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 team also found that cancer patients with higher levels of TexPSR in their T cells were less likely to respond well to immunotherapy. This connection suggests that targeting TexPSR could offer a new strategy for improving treatment outcomes.

"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 researchers showed that this ongoing cycle of protein stress drives T-cell exhaustion and prevents the immune system from functioning properly. They confirmed the same mechanism across several cancer types -- including lung, bladder, liver, and leukemia -- indicating that the process is widespread and potentially relevant to many forms of cancer.

Li and his colleagues published their findings in the journal Nature.