A Comprehensive Strategy Based on High Clinical Translational Nanosystem for Programmable Immunotherapy of Triple Negative Breast Cancer

Abstract Triple negative breast cancer (TNBCs), known as an immunologically cold tumor, is difficult to completely eliminate with existing monotherapies, let alone metastasis and recurrence. It is urgent to design a rational combination of multiple therapies to programmatically reconstitute tumor microenvironment (TME) and reverse the immune “cold” into “hot” inflammatory tumors to improve the therapeutic effect. Hence, in this work, a multifunctional nanosystem (FeSH NPs) that integrates metal‐polyphenol coordination complex as a photothermal agent and polyphenol, salvianolic acid B (SAB) as immunomodulator is designed and fabricated for synergistic photothermal‐immunotherapy of TNBCs combined with anti‐PD‐L1 antibody. Guided by photothermal/photoacoustic dual‐mode imaging, photothermal therapy (PTT) caused by FeSH NPs induces immunogenic cell death (ICD) under 808 nm laser irradiation. Subsequently, the loaded SAB is released with the addition of deferoxamine mesylate (DFO) to remodel TME, specifically TGF‐β inhibition and PD‐L1 upregulation, and eliminate the primary tumors. The combination of PTT and TME reprogramming by FeSH NPs further synergizes with anti‐PD‐L1 antibody to eradicate recurrence and inhibit metastasis of TNBCs concurrently. Given the biosafety of FeSH NPs throughout the lifecycle, this work provides a protocol with high clinical translational promise for comprehensive programmed therapeutics of immunologically cold tumors TNBCs.