Development of a Synergistic Photothermal-Immunotherapy Nanoplatform via Codelivery of a STING Agonist and Cyanine Dye against Triple-Negative Breast Cancer

The Stimulator of Interferon Genes (STING) pathway crucially modulates antitumor immunity and has therapeutic potential in aggressive triple-negative breast cancer (TNBC). Agonist-mediated STING activation triggers interferon-signaling cascades, which amplifies immune responses and enhances antitumor capabilities. Adjunctively, photothermal therapy (PTT) utilizes localized hyperthermia for tumor ablation and concurrently elicits immunogenic cell death (ICD), releases tumor-associated antigens, and activates acquired immune responses. We used an amphiphilic carrier material (PEI-GCP(Z)/mPEG) to coload cyanine dye (IR783) and the STING agonist (MSA-2), which self-assembled into the nanoparticle (PMI) and conferred three therapeutic advantages: (1) PTT-induced tumor-cell death and release of tumor-associated antigens; (2) STING agonist-based activation of innate immunity and enhanced dendritic cell maturation and antigen presentation; and (3) significantly improved cytotoxic T-lymphocyte responses with immune checkpoint blockade and nanoparticle-aided photothermal-immunotherapy. We evaluated the cellular synergistic antitumor effects <i>in vitro</i>. In a bilateral breast tumor model, after intravenous injection, PMI accumulated in tumors and induced significant ICD after laser irradiation, promoted antigen-presenting cell maturation, and activated cytotoxic T-cell antitumor-killing effects. PMI-anti-PD-L1 antibody blockade inhibited distant tumor growth through an excellent antitumor immune response. Combining STING pathway activation with PTT to achieve robust antitumor immunity offers an effective approach to TNBC therapy.