Stress-responsive immune microenvironment in triple-negative breast cancer among African American women

African American (AA) women experience higher incidence and mortality from triple-negative breast cancer (TNBC) compared to White women, particularly at younger ages. While socioeconomic determinants contribute to this disparity, emerging evidence indicates that chronic social stress becomes biologically embedded, reshaping systemic inflammation and the tumor immune microenvironment (TIME). We hypothesize that stress-responsive inflammatory signaling drives the accumulation of immune suppressive myeloid cell populations contributing mechanistically to enhanced cancer stemness and aggressive tumor behavior in AA TNBC.Using spatial transcriptomics on TNBC tumors from (n=4) AA and (n=4) White patients enrolled in the Karmanos Cancer Institute Biobank, we identified distinct immune and stress-response programs enriched in AA tumors. AA samples displayed a marked increase in immunosuppressive myeloid populations, including TAM-like and MDSC-like clusters, accompanied by heightened expression of IL1B, TNFA-associated cytokine modules, S100A8/S100A9, and other innate inflammatory cytokines. These inflammatory programs correlated with activation of stress-response pathways, most notably HSP70, a central regulator of cellular stress, danger signaling, and antigen presentation. Mechanistically, these pathways were tightly linked to a transcriptional activation of cancer stemness signatures, including NQO2, IRF3-associated stress modules, and other stem-associated genes, consistent with a more plastic, therapy-resistant phenotype in AA TNBC tumors.Previous studies have shown that chronic social stressors such as perceived discrimination, inadequate support, and neighborhood disadvantage have been associated with systemic inflammation and altered immune response. Our tumor-level analyses suggest that this stress activated signaling may converge on innate immune pathways within the TIME, amplifying myeloid suppression, cytokine activation, and stress-induced stemness that collectively worsened outcomes.Hypothesizing that AA patients experience higher social stress than White patients, these results support a mechanistic model in which psychosocial stress primes the innate immune microenvironment toward immune dysfunction and myeloid dominance, promoting tumor plasticity and metastatic potential in AA TNBC. Understanding how stress-responsive immunologic programs shape tumor evolution may reveal actionable targets to mitigate biologically mediated cancer disparities and guide interventions integrating immunology, social determinants, and precision oncology.