Targeting the tumor microenvironment with amphiphilic near-infrared cyanine nanoparticles for potentiated photothermal immunotherapy

Despite the potential of photothermal therapy (PTT) for cancer treatments, PTT alone has limitations in treating metastatic tumors and preventing tumor recurrence, highlighting the need to combine PTT with immunotherapy. This study reports tumor microenvironment (TME)-targeting, near-infrared (NIR) dye derivative—based nanomedicine for effective combined PTT—immunotherapy. Amphiphilic NIR dye cyanine derivatives are used not only for constructing the nanoparticle mass, but also for creating a stable complex with CpG adjuvant; a peptide specific to fibronectin extra domain B (APT EDB ) is also introduced as a TME-targeting ligand, yielding the TME-targeting nanomedicine, APT EDB -cyNP@CpG. APT EDB -cyNP@CpG shows cancer-targeting ability in EDB-overexpressing CT26 colon tumor-bearing mice. When combined with laser irradiation , it induces immunogenic cell death (ICD) and subsequently leads to significant increase in CD8 + T cell population in the tumor, resulting in greater antitumor therapeutic efficacy than does cyNP@CpG lacking the TME-targeting ligand. Moreover, the combination of APT EDB -cyNP@CpG–based PTT and an immune checkpoint blockade (ICB) antibody leads to remarkable antitumor efficacy against the laser-irradiated primary tumor as well as distant tumor through potentiation of systemic cancer cell-specific T cell immunity. Furthermore, the PTT-immunotherapy combination regimen is highly effective in inhibiting tumor recurrence and metastasis. This report describes the development of a near-infrared dye-based nanomedicine that targets an abnormal extracellular matrix component in tumor microenvironment (TME) for effective combined photothermal therapy-immunotherapy, which results in potent antitumor efficacy in a primary tumor as well as a distantly located secondary tumor.