Multifunctional nanodrug-enabled mild photothermal therapy for enhanced immunotherapy in triple-negative breast cancer

Abstract

Triple-negative breast cancer (TNBC) responds poorly to immune checkpoint blockade (ICB) based immunotherapy owing to the lack of immunogenicity as well as a highly immunosuppressive tumor microenvironment (TME). Mild photothermal therapy (PTT) can induce an immune-favorable tumor microenvironment and has been proposed to sensitize tumors to ICB therapy. Drawing from this concept, a novel multifunctional nanodrug, ICG@Tf–DTPA–Gd, was developed. This nanodrug, which combines transferrin (Tf) with Gd–DTPA and ICG, is designed for multimodal imaging-guided mild PTT, aiming to enhance immunogenicity and facilitate effective ICB immunotherapy in TNBC. When exposed to an 808 nm laser, the ICG@Tf–DTPA–Gd NPs exhibited exceptional photothermal performance, effectively triggered immunogenic cell death (ICD) and promoted the maturation of dendritic cells (DCs) in vitro. In vivo studies revealed strong multimodal imaging capabilities, consisting of magnetic resonance imaging (MRI), fluorescence imaging (FLI), and photothermal imaging. When used in combination with anti-programmed death-ligand 1 (PD-L1), this photo-immunotherapy system induced ICD and DC maturation, and increased the infiltration of cytotoxic T lymphocytes (CTLs) into tumors, which resulted in significant reduction in primary tumor foci and pulmonary metastases. As a result, this approach not only triggers a robust adaptive immune response but also transforms the immunologically “cold” TNBC into a “hot” tumor, enabling effective anti-PD-L1 therapy. This provides a promising alternative and valuable reference for effective immunotherapy of TNBC.