Hesperetin-Black Phosphorus Nanosheets Targeting TAMs Induce Ferroptosis and Reverse Protumoral Polarization to Remodel the Immune Microenvironment

This study focused on developing a novel nanodelivery system, BP-PEG-S2P@H, with hesperetin-loaded black phosphorus nanosheets to target tumor-associated macrophages (TAMs) in triple-negative breast cancer (TNBC). Through RNA sequencing and proteomic analyses, CEBPG upregulation was observed in TAMs, potentially controlling the SLC7A11-mediated ferroptosis pathway. In vitro and in vivo experiments, including FerroOrange and malondialdehyde assays, demonstrated the induction of ferroptosis by BP-PEG-S2P@H. The nanoplatform facilitated the transition of TAMs from the M2 to the M1 subtype, enhancing IL-12 secretion while reducing IL-10 levels. Functional analyses confirmed the reversal of the pro-migratory TAM phenotype and inhibition of tumor cell invasion. In vivo imaging validated efficient tumor targeting, with immunohistochemical staining revealing decreased CEBPG/SLC7A11 expression in tumors, reduced macrophage infiltration, and enhanced CD8 + T cell activation, promoting the efficacy of PD-L1 immunotherapy. Biosafety assessments indicated no apparent toxicity, supporting the potential of the BP-PEG-S2P@H nanoplatform for TAM-targeted nano-immunotherapy in TNBC.