Tumor emboli-associated adaptive stress response signatures identify aggressive disease features in inflammatory breast cancer.

Inflammatory breast cancer (IBC) is an aggressive breast cancer subtype characterized by tumor emboli, lymphovascular invasion (LVI), and early dissemination. Herein, we establish adaptive stress response (ASR) as a biologic feature linking stress adaptation to tumor emboli survival, lymphatic dissemination, therapeutic response, and disparities. Using a previously defined 226 ASR-related genes, complementary preclinical models of tumor emboli and lymphatic circulating cell clusters, and independent patient cohorts, we identified ASR genes enriched for XIAP-NFκB, oxidative stress response, inflammatory, and immune pathways. CXCL8 emerged as one of the most highly upregulated transcripts in tumor emboli and was shared across both models; however, CXCL8 , IL6 , and PTGS2 were downregulated in lymphatic circulating cell clusters and LVI-positive triple-negative IBC patients, suggesting dynamic remodeling of inflammatory signaling during dissemination. CYP4B1 was associated with ER status, LVI, and therapeutic response across multiple cohorts, implicating metabolic stress adaptation in dissemination. IL6 and PTGS2 were elevated in self-reported Black patients with triple-negative IBC compared to White patients. Pharmacologic inhibition of XIAP-NFκB and oxidative stress pathways suppressed tumor emboli formation. Collectively, these findings identify ASR signaling as a framework linking tumor emboli survival, dissemination, and therapeutic vulnerability in IBC.