Black phosphorus-based photothermal disruption of cancer-associated fibroblast barriers and tumor-associated macrophage targeting to enhance anti-PD-L1 immunotherapy in triple-negative breast cancer

Abstract

Triple-negative breast cancer (TNBC) remains a clinical challenge due to its high risk of recurrence and metastasis, coupled with limited responses to immunotherapy. Tumor-associated macrophages (TAMs) contribute to immunosuppression in the tumor microenvironment (TME) through C-X-C motif ligand 1 (CXCL1) secretion, but their targeting is hindered by poor drug delivery efficiency and physical barriers imposed by cancer-associated fibroblasts (CAFs). To address this, we developed a TAM-targeting black phosphorus nanosystem (αM2-BP-BHS, MBB) loaded with Baohuoside I (BHS), a known inhibitor of TAM polarization and CXCL1 secretion. In vitro and in vivo studies demonstrated that MBB efficiently targets TAMs and penetrates CAF barriers via photothermal activation under 808 nm near-infrared (NIR) irradiation, significantly enhancing BHS-mediated suppression of TAM/CXCL1 signaling. Furthermore, MBB-mediated photothermal therapy (PTT) boosted the memory T cell population, CD8⁺ T-cell infiltration and cytotoxic cytokine expression. When combined with anti-PD-L1 therapy, MBB synergistically suppressed TNBC progression and metastasis while establishing durable anti-cancer immunity to prevent recurrence. Notably, MBB exhibited excellent biocompatibility with minimal off-target effects, underscoring its potential as a precision delivery platform for BHS. Our findings highlight MBB as a promising adjuvant to potentiate immunotherapy in TNBC by concurrently overcoming stromal resistance and reprogramming immunosuppressive TME.