The ability of immune cells—particularly CD8+ T cells—to launch a rapid burst of proliferation inside tumors is key to the success of modern day cancer immunotherapies. However, the factors and mechanisms that drive this burst in proliferation remain poorly understood, making it difficult to predict which patients will benefit from treatment. A deeper understanding of this T cell burst could also guide the development of new therapies that enhance T cell proliferation and improve treatment outcomes.
To tackle this challenge, an international team of researchers led by Associate Professor Satoshi Ueha and Professor Kouji Matsushima from the Research Institute for Biomedical Sciences, Tokyo University of Science (TUS), Japan, developed a novel approach to monitor CD8⁺ T cell activity over time. Their findings, recently published in the journal Nature Communications on October 20, 2025, sheds new light on how T cells expand in the tumor—and how their expansion can be predicted, and ultimately, therapeutically reactivated.
“The development of immunotherapies has been hindered by our inability to comprehensively monitor their effects on immune cells—particularly cancer-fighting T cells—over time,” explains Dr. Ueha. “Building on our previous work, we developed a method to track these cells longitudinally in the tumor, allowing us to gain deeper insights into the burst of proliferation that drives effective anti-tumor responses.”
The researchers created a ‘multi-site tumor model’ in mice, implanting tumors at different anatomical locations to allow for sequential sampling of T cells over time. By using unique T cell receptor (TCR) sequences as natural barcodes, the team was able to track hundreds of individual CD8⁺ T cell clones as they expanded or contracted over a week—yielding a dynamic, clonal-level view of the immune response to cancer that had previously been out of reach.
Using next-generation single-cell RNA and TCR sequencing, the team discovered that expanding T cells consistently expressed a specific set of genes prior to proliferation. This coordinated gene set—called the “expansion signature”—could identify T cells that were primed for growth. The expansion signature proved to be a strong predictor of T cell expansion in both untreated and immunotherapy-treated mice, including those receiving programmed cell death-ligand protein 1 and cytotoxic T-lymphocyte associated protein 4 or lymphocyte activation gene-3 (LAG-3) checkpoint blockade therapy. Notably, its expression in human patients receiving various immunotherapies, including programmed cell death protein 1 blockade and chimeric antigen receptor-T cell therapy correlated with improved survival outcomes.
While the expression of expansion signature faded over time, prior to T cell contraction, the researchers found that a specific population of T cells with the potential to reignite expansion remained within the tumor. To test this, the team administered LAG-3 blockade and observed reactivation of the expansion signature along with renewed proliferation of previously contracted T cell clones.
These findings position the expansion signature as a powerful pan-immunotherapy biomarker for tracking, predicting, and potentially reinvigorating the anti-tumor T cell response. “Our work opens the door to a dynamic understanding of how immunotherapies succeed or fail in real time,” says Dr. Ueha. “We hope that the expansion signature can serve not only as a predictor of treatment response but also as a guide for designing new therapies that can reawaken the immune system when it begins to falter. Ultimately, this could bring us closer to truly personalized immunotherapy.” The researchers hope that the expansion signature will ultimately pave the way for the development of new therapies that modulate immune cell dynamics. Tuning T cell proliferation provides a granular control of the immune response that could both maximize treatment efficacy and minimize the effect of adverse events .
In summary, this study captures the T cell expansion dynamics that are critical for the success of cancer immunotherapies. By uncovering the genetic signature that predicts and even helps reinvigorate T cell proliferation, the researchers provide a powerful pan-immunotherapy biomarker for treatment monitoring that opens the doors to the development of next-generation immunodynamic therapies.
***
Reference
DOI: https://doi.org/10.1038/s41467-025-64107-5
About The Tokyo University of Science
Tokyo University of Science (TUS) is a well-known and respected university, and the largest science-specialized private research university in Japan, with four campuses in central Tokyo and its suburbs and in Hokkaido. Established in 1881, the university has continually contributed to Japan's development in science through inculcating the love for science in researchers, technicians, and educators.
With a mission of “Creating science and technology for the harmonious development of nature, human beings, and society", TUS has undertaken a wide range of research from basic to applied science. TUS has embraced a multidisciplinary approach to research and undertaken intensive study in some of today's most vital fields. TUS is a meritocracy where the best in science is recognized and nurtured. It is the only private university in Japan that has produced a Nobel Prize winner and the only private university in Asia to produce Nobel Prize winners within the natural sciences field.
Website: https://www.tus.ac.jp/en/mediarelations/
About Associate Professor Satoshi Ueha from Tokyo University of Science
Dr. Satoshi Ueha is an Associate Professor at the Research Institute for Biomedical Sciences, Tokyo University of Science, Japan. Dr. Ueha specializes in tumor immunology, inflammation, chemokines, and transplantation immunology. In addition to publishing 193 papers that have been extensively read and cited, he holds 13 research patents, including one that has been granted for an invention that can predict the effects of cancer treatment using immune checkpoint inhibitors. In recent years, he has also served as a councilor in the Japanese Society for Immunology and as the recommended secretary of the Japanese Society of Interferon & Cytokine Research.
Funding information
This work was supported by the Japan Society for the Promotion of Science under grants 20H03474 and 23K27397, and by the Japan Agency for Medical Research and Development under grants JP22fk0310509 and JP25fk0310531, and JP22ama221306.
END