Hypoxia Alleviation-Potentiated Chemotherapy Enhances Anti-PD-L1 Treatment for Triple-Negative Breast Cancer via Improving Tumor Immunogenicity and Inhibiting STAT3 Activation

The combination of anti-PD-L1 and paclitaxel (PTX) is a standard-of-care regimen for triple-negative breast Cancer (TNBC). However, TNBC is classified as a ″cold″ tumor characterized by low immunogenicity, hypoxia, and the aberrant activation of signal transducer and activator of transcription 3 (STAT3), which greatly reduces the efficacy of immune checkpoint blockades (ICBs). This project aims to construct an albumin-based nanomedicine coloaded with atovaquone (ATO) and PTX for targeted tumor delivery, thereby enhancing the therapeutic efficacy of ICBs. The nanomedicine exhibits optimal particle size, exceptional stability, excellent biocompatibility, and a high drug encapsulation efficiency. Among these, ATO enhances PTX-induced immunogenic cell death by alleviating tumor hypoxia, thereby increasing tumor immunogenicity. Furthermore, ATO reduces STAT3 phosphorylation, modulating the immunosuppressive tumor microenvironment. The combination of nanomedicine with ICBs synergistically transforms TNBC from an immunologically ″cold″ to a ″hot″ tumor. This transformative approach significantly enhances the therapeutic efficacy of combination chemotherapy, leading to potent suppression of primary tumors while concurrently preventing postoperative recurrence and pulmonary metastases. This project has the potential to introduce innovative strategies and methodologies aimed at overcoming the limited efficacy of PTX combined with ICBs in the treatment of TNBC.

hypoxia; immune checkpoint blockades; immunogenic cell death; triple-negative breast cancer; tumor microenvironment.