Groundbreaking Study Maps Complex Interplay Between Cells, Metabolism, and Immunity in Breast Cancer Lymph Node Metastasis

A recent integrative analysis of single-cell sequencing and single-cell spatial mapping of lymph node metastasis in breast cancer reveals novel mechanisms of the metabolic-immune interaction that drive the spread of breast cancer. The findings from the study in The American Journal of Pathology, published by Elsevier, offer novel insights into the characteristics of the metastatic tumor microenvironment, providing a foundation for targeted therapeutic strategies.

Breast cancer remains the second most frequently diagnosed cancer globally and accounts for approximately 23.8% of cancer cases among women. It is a leading threat to women’s health, with lymph node metastasis a critical factor contributing to poor patient prognosis. Yet our understanding of the molecular mechanisms driving lymph node metastasis has been limited.

A collaborative team of researchers has now constructed the comprehensive “cell-metabolism-immunity” landscape of the breast cancer lymph node metastatic microenvironment by integrating single-cell RNA sequencing and spatial transcriptomics. This advanced tool precisely maps the activity of thousands of genes in their original locations. Researchers analyzed single-cell data from 78 paired primary breast cancer and lymph node metastasis samples, encompassing over 360,000 cells. Ten major cell types were identified, including epithelial cells, immune cells, and stromal cells.

“By combining advanced genetic sequencing and spatial mapping, we have gained unprecedented insights into the dynamic changes and cellular communication patterns within the metastatic microenvironment,” explains lead investigator Li Guo, PhD, State Key Laboratory of Flexible Electronics (LoFE) & Institute of Advanced Materials (IAM), School of Chemistry and Life Sciences, Nanjing University of Posts and Telecommunications, Nanjing, China.

Key drivers of metastasis: Early disseminated cancer cells (EDCs)

High-resolution clustering revealed a unique subpopulation of early disseminated cancer cells (EDCs) within epithelial cells. These EDCs exhibit enhanced invasive and metastatic capabilities through metabolic reprogramming (e.g., hypoxia response and glycolysis activation) and immune modulation, thereby establishing a microenvironment that facilitates tumor cell survival and suppresses immune function to accelerate metastasis.

Cellular communication network analysis uncovered a sophisticated three-way interaction between lymphocytes, macrophages, and epithelial cells in the metastatic microenvironment. Specifically, M2-type macrophages secrete cytokines like CCL22 and CXCL12, inducing an immunosuppressive microenvironment while driving malignant transformation of EDCs. Spatial transcriptomics validated that these interactions form distinct spatial regions in lymph node tissues, overlapping with the tumor invasion front.

“This systemic interaction between cancer cells, metabolism, and immunity is the core mechanism of lymph node metastasis and a potential therapeutic target,“ says co-lead investigator Tingming Liang, PhD, School of Life Science, Nanjing Normal University, Nanjing, China.

Novel strategies for precision therapy

The researchers identified four tyrosine kinase inhibitors targeting M2 macrophages, including pexidartinib hydrochloride and sunitinib malate. These drugs block immunosuppressive macrophage function by inhibiting key targets like CSF1R, thereby suppressing lymph node metastasis.

"These drugs have demonstrated safety in treating other cancers, and our findings provide a theoretical basis for their application in breast cancer metastasis," notes Dr. Guo. “Future work will need to explore the metabolic vulnerabilities of EDCs and integrate clinical data to advance the development of innovative therapeutic strategies for patients.”

Notes for editors

The article is “Deciphering the Cellular and Metabolic Landscape of Lymph Node Metastasis in Breast Cancer Using Single-Cell and Spatial Multi-Omics,” by Rui Zhu, Guijie Jiang, Jie Shen, Chengxuan Gong, Hongyu Shan, Tingming Liang, and Li Guo (https://doi.org/10.1016/j.ajpath.2026.01.002). It appears in The American Journal of Pathology, volume 196, issue 4 (April 2026), published by Elsevier.

The article is openly available for 60 days at https://ajp.amjpathol.org/article/S0002-9440(26)00007-6/fulltext.

Full text of the article is also available to credentialed journalists upon request. Contact Eileen Leahy at +1 732 406 1313 or [email protected] to request a PDF of the article or more information. To reach the study’s authors contact Tingming Liang, PhD, at [email protected].

This study was supported by the National Natural Science Foundation of China project numbers 62571264 and 62171236, the key project of social development in Jiangsu Province project number BE2022799, the key projects of Natural Science Research in Universities of Jiangsu Province project number 22KJA180006, the Qinglan Project of Jiangsu Universities in Jiangsu Province, the Postgraduate Research and Practice Innovation Program of Jiangsu Province project number SJCX25_0737, and the Priority Academic Program Development of Jiangsu Higher Education Institution.

About The American Journal of Pathology

The American Journal of Pathology, official journal of the American Society for Investigative Pathology, published by Elsevier, seeks high-quality original research reports, reviews, and commentaries related to the molecular and cellular basis of disease. The editors will consider basic, translational, and clinical investigations that directly address mechanisms of pathogenesis or provide a foundation for future mechanistic inquiries. Examples of such foundational investigations include data mining, identification of biomarkers, molecular pathology, and discovery research. High priority is given to studies of human disease and relevant experimental models using molecular, cellular, and organismal approaches. ajp.amjpathol.org

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