Prolonged illnesses such as cancer and chronic infections weaken the immune system, leaving its key defenders-T cells, fatigued and ineffective. However, a study led by the Peter Doherty Institute has identified a rare subset of immune cells, called stem-like T cells, that play a crucial role in maintaining long-term immune responses.
Published in Science Immunology, the study highlights the importance of a protein known as ID3, produced by the gene of the same name. ID3+ T cells possess a unique ability to self-renew and resist exhaustion, allowing them to sustain immune responses significantly longer than their counterparts lacking ID3 expression. These findings present new opportunities for enhancing immunotherapy and developing more effective treatments for cancer and chronic infections.
Graca et al. emphasized the significance of these findings and stated that ID3+ T cells have the remarkable ability to resist burnout and maintain a powerful immune response over time, making them particularly effective against chronic infections and cancer.
One of the major challenges in immunotherapy is overcoming T cell exhaustion, particularly in treatments like CAR T cell therapy, which, although transformative, loses efficacy over time due to T cell fatigue. This study found that specific inflammatory signals in the body could enhance ID3+ T cell formation, potentially revolutionizing therapeutic strategies.
The researchers noted that enhancing ID3 activity could extend the endurance of T cells, making cancer treatments more durable and effective. They found that ID3+ T cell formation could be stimulated by particular inflammatory cues, offering new approaches to boost the immune system’s ability to fight cancer.
Jin et al. suggested that ID3 plays a crucial role in maintaining the functionality of CD8 T cells within the tumor microenvironment, thereby enhancing anti-tumor immunity. Another study by Good et.al also found that silencing the proteins ID3 and SOX4 in CAR T cells helped these cells retain much of their tumor-killing effectiveness even after prolonged exposure to tumors. This suggests that inhibiting ID3 and/or SOX4 might enhance the efficacy of CAR T cell therapies against solid tumors.
The researchers emphasized the broader implications of their findings, particularly in addressing the persistent challenge of immune cell exhaustion in chronic diseases. By identifying ID3 as a critical regulator of T cell responses, the study offers a promising approach to reinvigorating the immune system and enhancing immunotherapy outcomes for cancer, HIV, and hepatitis B and C. Modulating IL-1 cytokines or enhancing ID3 expression could pave the way for more effective and durable T cell-based treatments, reshaping therapeutic strategies for chronic conditions and advancing global healthcare solutions.
References
- Gago da Graça C, Sheikh AA, Newman DM, Wen L, Li S, Shen J, et al. Stem-like memory and precursors of exhausted T cells share a common progenitor defined by ID3 expression. Science Immunology. 2025 Jan 31;10(103):eadn1945.
- Jin Y, Hu P, Sun H, Yang C, Zhai J, Wang Y, et al. Expression of Id3 represses exhaustion of anti-tumor CD8 T cells in liver cancer. Mol Immunol. 2022 Apr;144:117–26.
- Good CR, Aznar MA, Kuramitsu S, Samareh P, Agarwal S, Donahue G, et al. An NK-like CAR T cell transition in CAR T cell dysfunction. Cell. 2021 Dec 9;184(25):6081-6100.e26.