Researchers Discover Why Cancer Immunotherapy Could Be Failing 

A new study from Ohio State University Wexner Medical Center has discovered why immunotherapy fails in 60-80% of cancer patients. Researchers identified a previously unknown stress pathway called TexPSR that floods weakened immune cells with misfolded proteins, crippling their ability to attack tumors. Blocking this pathway in laboratory models restored immune cell function and significantly improved immunotherapy effectiveness across multiple cancer types. 

Immune system T cells recognize and fight infections and cancer, but often become weakened and lose effectiveness during prolonged battles with tumors. The Ohio State team found these depleted T cells collapse under misfolded proteins that trigger TexPSR, a stress response that paradoxically drives protein production into overdrive. 

Normal cellular stress responses slow protein creation to help cells recover, but TexPSR does the opposite, creating relentless buildup of damaged proteins and toxic clumps similar to plaques seen in Alzheimer’s disease. 

Nature Reviews Immunology described this as proteotoxic shock. When researchers blocked key TexPSR drivers in laboratory models, weakened T cells recovered their function and immunotherapy became markedly more effective. The mechanism operated consistently across lung, bladder, liver cancer, and leukemia, suggesting the stress response impacts immunotherapy effectiveness across several types of cancer. 

Dr. Zihai Li, senior study author and founding director of the Pelotonia Institute for Immuno-oncology (PIO) at Ohio State, has studied protein folding and immunity connections for over three decades. Li noted that scientists worldwide tackle weakened T-cell function through genetics, metabolism, and other approaches, but protein quality control has been largely overlooked. 

He emphasized that T-cell depletion represents the biggest roadblock to cancer immunotherapy, and these results could prove critical for improving engineered cancer treatments. High TexPSR levels in T cells from cancer patients correlated with poor immunotherapy responses, indicating that targeting this pathway could enhance treatment outcomes. 

First author Yi Wang explained that weakened T cells continue creating molecular weapons but destroy those weapons before they can function. This self-perpetuating protein stress cycle drives T-cell failure and ultimately disables immune system function against tumors. 

The findings published in the journal Nature could help the majority of cancer patients who currently don’t respond to immunotherapy. The groundbreaking discovery reveals that weakened immune cells aren’t simply tired or depleted of resources, but actively poisoned by their own malfunctioning protein production systems. 

Targeting this newly identified vulnerability could transform how doctors approach cancer treatment, potentially converting immunotherapy from a therapy that helps only 20-40% of patients into one that benefits the majority struggling with malignancies that currently evade immune system attacks. 

As companies like Calidi Biotherapeutics Inc. (NYSE American: CLDI) undertake R&D programs aimed at commercializing novel immunotherapies, the insights gained from the study on malfunctioning protein production systems could aid the therapy development process. 

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