T cells are crucial components of our immune system, serving as critical protectors against infection and disease.
But there are limits to their defensive capabilities. T cells are not inexhaustible protectors. Often, when T cells have engaged in killing tumor cells, they burn out and lapse into a dysfunctional state known as T cell exhaustion. Rebounding from exhaustion — or avoiding it altogether — would greatly aid their disease-fighting success. Today, rescuing T cells from burnout and getting them back into cancer-fighting shape is a major focus of cancer immunotherapy efforts.
New research published in the journal Cell and led by Professor Ananda Goldrath’s lab in the University of California San Diego School of Biological Sciences has uncovered an unexpected factor in our current understanding of T cell exhaustion.
Protein homeostasis, or “proteostasis,” is a network of cellular processes that orchestrates the proper construction, movement and destruction of proteins in cells. One component of this network features a type of recycling function within cells. Healthy cells continuously dismantle old and damaged proteins to preserve energy and reuse building blocks to make new proteins.
Led by Postdoctoral Fellow Nicole Scharping in Goldrath’s Lab and including scientists from La Jolla Institute for Immunology and University of Arkansas for Medical Science, the study, featured on the cover of Cell , uncovered an impaired protein recycling function as the surprise culprit in T cell exhaustion.
“We found that exhausted T cells’ recycling programs are falling apart, leading to damaged and misfolded proteins that pile up with nowhere to go,” said Scharping. But the research also uncovered a way to reverse the accumulation of misfolded proteins by fixing the broken recycling function and restoring normal proteostasis. Scharping said the issue can be resolved with a “tag and sort” fix. A family of enzymes called E3 ligases acts as labelers at a recycling facility, tagging worn-out proteins so the cell knows to break them down.
“In exhausted T cells, many of these enzymes get switched off, and recycling grinds to a halt,” said Scharping. “When we restored specific E3 ligases, the buildup cleared, and the T cells regained their function and worked better at clearing tumors.”
Impaired protein processing is not unique to dysfunctional T cells, the researchers note. The findings hint that impaired protein recycling may tie together the biological process for diseases that are otherwise unrelated.
“We think this loss of proteostasis resembles what occurs in neurons in other protein aggregate diseases such as Parkinson’s and Alzheimer’s,” said Goldrath, a professor in the Department of Molecular Biology. “Rescuing these cells from exhaustion could improve the ability of T cells to respond to both chronic infection as well as tumors.”
The findings were aided by the use of mass spectrometry, an advanced analytical method that identifies and measures the mass of molecules, led by Professor Eric Bennett’s lab at UC San Diego (Department of Cell and Developmental Biology) and Global Autoimmune Institute Assistant Profesor Samuel Myers' lab a La Jolla Institute for Immunology. Mass spectrometry offered the ability to simultaneously examine thousands of proteins and suggest NEURL3, RNF149 and WSB1 as the E3 ligases responsible for rescuing T cell recycling functions.
With these ligases back in place and the protein accumulation blockade cleared, the researchers found that they could boost the potency of cell therapy against cancer. While the new study was conducted in mice, the researchers indicate that similar strategies could be employed for immunotherapy treatments in human cancer.
“We uncovered one of the mechanisms by which T cells lose their ability to fight cancer and now we have a target that we can use to design interventions to improve responses to immunotherapy as well as prevent chronic infection,” said Goldrath.
Cell
Experimental study
Animals
Proteostasis sustains T cell differentiation potential and tumor-infiltrating lymphocyte function
29-Apr-2026
Amir Ferry is a co-founder, CEO and board member of TCura Bioscience. Ananda Goldrath is a co-founder of TCura Bioscience, Inc., serves on the scientific advisory board of Foundery Biosciences and is a senior advisor to the Allen Institute for Immunology.