Inhibition of Tumor Microenvironment-Driven JAK-STAT Signaling Enhances Response to Arginine Deprivation Therapy in Triple-Negative Breast Cancer
Year: 2025
Type: article
Abstract: Argininosuccinate synthetase 1 (ASS1) expression and arginine availability are key metabolic determinants that influence tumor fitness and regulate immune interactions within the tumor microenvironment (TME). Using an orthotopic triple-negative breast cancer (TNBC) model, we demonstrate that arginine deprivation heightens tumor dependence on the TME for survival. Mechanistically, fibroblasts sustain tumor viability by supplying arginine, whereas macrophages cooperate with stromal cues to activate Janus kinase-signal transducer and activator of transcription (JAK-STAT) signaling, thereby enhancing tumor survival. Concordantly, a JAK-STAT gene-expression signature correlates with ASS1 levels in human TNBC datasets. Translationally, combined pharmacological inhibition of JAK signaling with arginine deprivation markedly suppresses tumor growth. Together, these findings reveal a TME-driven, targetable stromal-immune circuit that enables tumors to withstand arginine deficiency-induced metabolic stress. Broadly, our work highlights that mapping and strategically inducing metabolic dependencies can reveal actionable compensatory pathways, offering opportunities to improve cancer therapy.
Source: Cells
Authors: Hila Tishler, Shahar Ziman, Kuoyuan Cheng, Kun Wang, Neel Sanghvi, Lital Adler, Gil Stelzer, Hillary Maniriho, Bareket Dassa, Elizabeta Bab-Dinitz, Michal Levi, Sivan Galai, Omer Goldman, Yarden Ariav, Naama Darzi, Saar Ezagouri, Nitsan Nimni, Nataly Rosenfeld, Ron Rotkopf, Alexander Brandis, Tevie Mehlman, Roni Oren, Mirie Zerbib, Yuri Kuznetsov, Sara Donzelli, Giovanni Blandino, Rony Seger, Eytan Ruppin, Ayelet Erez
Institutions: Weizmann Institute of Science, National Institutes of Health, National Cancer Institute, Center for Cancer Research, University of Illinois Urbana-Champaign, Cancer Center at Illinois, Tel Aviv University, Istituti di Ricovero e Cura a Carattere Scientifico, Instituto Nazionale Tumori Regina Elena
Language: English
Subfield: Biotechnology
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $3,258
OpenAlex ID: W7116834113