A tumor-targeted heptamethine cyanine dye suppresses triple-negative breast cancer by induction of lethal autophagy.

Abstract

Background: Triple-negative breast cancer (TNBC) is a highly invasive type of breast cancers that is characterized by the absence of hormone receptors and HER2 protein, thereby relying mostly on surgical intervention and cytotoxic chemotherapy. Recently, autophagy in TNBC progression has emerged as an important role for more effective TNBC treatments.

Methods: Since autophagy is a critical determinant of cell fate, depending on the context and stress level, we newly develop a hydrophilic anionic heptamethine cyanine dye (named TNBC800) for the treatment of TNBC by induction of lethal autophagy.

Results: TNBC800 induces autophagy-mediated immunogenic cell death to exert targeted therapeutic effects on MDA-MB-231 xenografts. In terms of molecular mechanism, the TNBC800 can be imported into MDA-MB-231 cells through the endosomal sorting complex required for transport (ESCRT) pathway. Consequently, TNBC800 elevates the intracellular level of reactive oxygen species (ROS) and induces autophagic stress, demonstrated by increased LC3B accumulation, which contributes to cell apoptosis and suppression of tumor proliferation. Finally, we confirm a substantial increase in the presence of M1 macrophages in spleen and NK cells in tumors over the course of treatment.

Conclusion: This study introduces a potentially effective strategy for enhancing TNBC treatment efficacy.