Hydroxy-Safflower Yellow A Inhibits Breast Cancer Growth via Tumor-Associated Macrophages/CCL5/Tissue Resident Memory T Cell Signaling

Abstract

Hydroxy-safflor yellow A (HSYA), a bioactive compound from Carthamus tinctorius, has reported anti-inflammatory and antitumor activities. However, its effects on breast cancer and the underlying immune mechanisms remain poorly defined. In this study, we investigated the immunomodulatory role of HSYA in breast cancer, with a focus on its impact on tumor-associated macrophages (TAMs) and T cell responses. Using in vitro assays, murine breast cancer models, and single-cell transcriptomic analysis, we found that HSYA significantly inhibited tumor growth and reshaped the tumor immune microenvironment. Flow cytometry and transcriptomic profiling revealed that HSYA treatment reduced tumor-associated macrophages (TAMs) infiltration and suppressed C-C motif chemokine ligand 5 (CCL5) expression, which was associated with enhanced recruitment and activation of tissue-resident memory T (TRM) cells. Co-culture and functional assays further supported a role for the TAM/CCL5 axis in mediating these immune effects. Collectively, our findings demonstrate that HSYA exerts antitumor activity, at least in part, by modulating the TAM/CCL5/TRM axis, highlighting its potential as an immunomodulatory therapeutic strategy in breast cancer.