Inhibition of Tumor Microenvironment-Driven JAK-STAT Signaling Enhances Response to Arginine Deprivation Therapy in Triple-Negative Breast Cancer

Highlights: What are the main findings? Arginine depletion suppresses TNBC cell growth in vitro but not in vivo, due to a TME-mediated arginine supply and JAK-STAT activation. ASS1 expression in human TNBC tumors correlates with JAK-STAT gene expression. Combining JAK inhibition with arginine depletion significantly suppresses tumor growth. What are the implications of the main findings? ASS1 expression may help identify breast tumors with active cytokine/JAK-STAT signaling and refine patients’ stratification for targeted therapies. Inducing metabolic vulnerability through arginine depletion uncovers a targetable TME-driven survival mechanism, suggesting a new potential immunotherapeutic approach for TNBC. 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.