New research reveals that keeping lymph nodes intact, which are often removed near tumors to prevent cancer from spreading, may lead to better patient outcomes and enhance the effectiveness of immunotherapies.
A research team led by the Peter Doherty Institute for Infection and Immunity (Doherty Institute) investigated the cellular and molecular processes that highlight the central role of lymph nodes in defending the body against chronic infections and cancer.
Their findings, published in two separate papers in Nature Immunology, demonstrated that lymph nodes create the optimal conditions for stem-like T cells—an important subset of immune cells—to persist, expand, and generate killer cells capable of targeting cancer or viral infections. Other immune organs, such as the spleen, lack this supportive environment, meaning these cells fail to develop or multiply as effectively there. This makes lymph nodes critical for mounting a robust immune response and for the success of immunotherapies.
Training grounds for T cells
The University of Melbourne’s Professor Axel Kallies, Laboratory Head at the Doherty Institute and senior author of both papers, said the findings have important implications for cancer therapy.
“Lymph nodes aren’t just passive waiting rooms for immune cells, they actively train and educate T cells, and send them off to do their job,” said Professor Kallies.
“Our research suggests that removing lymph nodes during cancer surgery, a common practice to prevent tumor spread, may inadvertently reduce the effectiveness of treatments, such as checkpoint blockade and CAR T cell therapies. Preserving lymph nodes could strengthen immune responses and increase the effectiveness of immunotherapy.”
Why patients respond differently
This research may also provide insight into why some patients benefit more from immunotherapy than others. The condition and performance of lymph nodes determine how effectively the immune system can generate cancer-fighting T cells, which in turn directly shapes the success of these treatments.
The University of Melbourne’s Dr. Carlson Tsui, Postdoctoral Researcher at the Doherty Institute and first author of one of the papers, said the findings could help to develop new strategies to make immunotherapy more effective.
“Our research identifies molecular signals that are involved in the regulation of stem-like cells and in their capacity to produce effective killer cells. These findings could guide the development and refinement of immune-based treatments for cancer and chronic infection,” said Dr. Tsui.
“Furthermore, our research shows that rather than only focusing on the tumor itself, therapies should also be designed to preserve and enhance lymph node function. By targeting these critical immune hubs, we could boost the body’s natural ability to fight cancer, increase the effectiveness of existing immunotherapies and help more patients respond to treatment.”
Toward clinical applications
Taken together, the two peer-reviewed studies offer new insights into how lymph nodes influence immune responses. Although the findings are based on animal models, they are expected to inform the development of future treatment strategies for chronic infections and cancer.
Professor Shahneen Sandhu, Research Lead for the Melanoma Medical Oncology Service at the Peter MacCallum Cancer Centre, commented on the clinical implications of this work.
“While this research was done in the laboratory with pre-clinical models, we’re excited to study these findings in clinical samples from patients receiving immune checkpoint inhibitors, as part of an ongoing Melanoma Research Victoria collaboration with Professor Kallies,” Professor Sandhu said.
“Combining clinical and preclinical studies will help us translate these discoveries from bench to bedside and back, ultimately improving outcomes for cancer patients.”
References:
“Lymph nodes fuel KLF2-dependent effector CD8+ T cell differentiation during chronic infection and checkpoint blockade” by Carlson Tsui, Leonie Heyden, Lifen Wen, Catarina Gago da Graça, Nikita Potemkin, Aleksej Frolov, Daniel Rawlinson, Lei Qin, Verena C. Wimmer, Marjan Hadian-Jazi, Darya Malko, Chun-Hsi Su, Sining Li, Kayla R. Wilson, Helena Horvatic, Sharanya K. Wijesinghe, Marcela L. Moreira, Lachlan Dryburgh, Dominik Schienstock, Lisa Rausch, Daniel T. Utzschneider, Cornelia Halin, Scott N. Mueller, Marc D. Beyer, Sammy Bedoui, Zeinab Abdullah, Jan Schröder and Axel Kallies, 15 September 2025, Nature Immunology.
DOI: 10.1038/s41590-025-02276-7
“Lymph-node-derived stem-like but not tumor-tissue-resident CD8+ T cells fuel anticancer immunity” by Sharanya K. M. Wijesinghe, Lisa Rausch, Sarah S. Gabriel, Giovanni Galletti, Marco De Luca, Lei Qin, Lifen Wen, Carlson Tsui, Kevin Man, Leonie Heyden, Teisha Mason, Lewis D. Newland, Andrew Kueh, Yang Liao, David Chisanga, Julian Swatler, Emanuele Voulaz, Giuseppe Marulli, Valentina Errico, Agnese Losurdo, Gustavo R. Rossi, Fernando Souza-Fonseca-Guimaraes, Nicholas D. Huntington, Thomas Gebhardt, Daniel T. Utzschneider, Marco J. Herold, Wei Shi, Jan Schroeder, Enrico Lugli and Axel Kallies, 29 July 2025, Nature Immunology.
DOI: 10.1038/s41590-025-02219-2
This work was supported by the National Health and Medical Research Council of Australia (NHMRC), the Australian Research Council (ARC), Cancer Council Victoria, EMBO, the Fondazione Italiana per la Ricerca sul Cancro-Associazione Italiana per la Ricerca sul Cancro, the German Research Foundation, the Helmholtz Association, Humanitas Research Hospital, the National Collaborative Research Infrastructure Strategy (NCRIS), Phenomics Australia and the University of Melbourne.
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