Prolonged illnesses like cancer and chronic infections often leave the immune system in a state of exhaustion, where its frontline defenders – T cells – lose their ability to function effectively. Research, led by the Peter Doherty Institute for Infection and Immunity ( Doherty Institute ) and the Peter MacCallum Cancer Centre ( Peter Mac ), have identified a rare type of immune cells, called stem-like T cells, that holds the key to maintaining powerful, long-term immune responses.
Published in Science Immunology , the study revealed that the endurance of these stem-like T cells is fuelled by a protein called ID3, expressed by a gene of the same name. These ID3+ T cells have a unique ability to self-renew and resist exhaustion, giving them the power to sustain immune responses far longer than other T cells that don't express ID3.
The University of Melbourne's Catarina Gago da Graça, PhD Candidate at the Doherty Institute, said the research highlights how ID3+ T cells hold the key to overcoming one of the biggest challenges in treating chronic diseases—immune exhaustion.
"ID3+ T cells have the remarkable ability to resist burnout and maintain a powerful immune response over time, making them particularly effective in the face of chronic infections or cancer," said and co-first author Gago da Graça.
The research also found that certain signals in the body could increase the number of ID3+ T cells, paving the way for improved treatments like CAR T cell therapy. While CAR T therapy has been transformative in treating certain cancers, its effectiveness can wane over time due to T cell exhaustion.
Professor Ricky Johnstone , Executive Director Cancer Research at Peter Mac and co-lead author of the study, said enhancing ID3 activity could strengthen the endurance of these cells, making therapies more effective and long-lasting.
"We discovered that ID3+ T cell formation could be promoted by specific inflammatory cues, potentially offering new strategies to boost the number of immune cells that excel at fighting cancer in patients," said Professor Johnstone.
"This could lead to better treatments for cancer patients and improve clinical immunotherapy outcomes."
The University of Melbourne's Dr Daniel Utzschneider , Laboratory Head at the Doherty Institute, said the findings could lead to advancements in immunotherapy treatments and the development of vaccines that provide long-lasting protection.
"Exhausted immune cells remain one of the biggest challenges in treating chronic diseases," said Dr Utzschneider.
"This research provides a roadmap for how we might reinvigorate the immune system to improve health outcomes for people living with cancer or chronic infections like HIV or hepatitis B and C, thanks to these stem-like T cells, the immune system's secret power."
This research is the result of a collaborative effort between the Doherty Institute, Peter Mac, La Trobe University, Northwestern University (USA), the Olivia Newton-John Cancer Research Institute, the University of Birmingham (UK) and the University of Melbourne.
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Additional information:
- Peer-reviewed paper: Gago da Garça C, Sheikh A, Newman D et al. Stem-like memory and precursors of exhausted T cells share a common progenitor defined by ID3 expression. Science Immunology (2025). DOI: https://doi.org/10.1126/sciimmunol.adn1945
- Funding: This work was supported by the National Health and Medical Research Council of Australia (NHMRC), the CASS Foundation, the Cancer Council Victoria and the Kids' Cancer Project, the UK Research & Innovation the University of Melbourne, the Clive and Vera Ramaciotti Foundation, the J & M Wright Foundation and CSL.
- Collaboration: This study is the result of a collaborative effort between the Doherty Institute, Peter Mac, La Trobe University, Northwestern University (USA), the Olivia Newton-John Cancer Research Institute, the University of Birmingham (UK) and the University of Melbourne.
About the Peter Doherty Institute for Infection and Immunity (Doherty Institute)
Finding solutions to prevent, treat and cure infectious diseases and understanding the complexities of the immune system requires innovative approaches and concentrated effort. This is why The University of Melbourne – a world leader in education, teaching and research excellence – and The Royal Melbourne Hospital – an internationally renowned institution providing outstanding care, treatment and medical research – have partnered to create the Peter Doherty Institute for Infection and Immunity (Doherty Institute); a centre of excellence where leading scientists and clinicians collaborate to improve human health globally. https://doherty.edu.au
About Peter Mac
Peter MacCallum Cancer Centre (Peter Mac) is a world leading cancer research, education and treatment centre and Australia's only public health service dedicated to caring for people affected by cancer. Based in Melbourne, Victoria we have 3,900 employees, including more than 750 laboratory and clinical researchers, all focused on providing better treatments, better care and potential cures for cancer. https://www.petermac.org
