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Abstract
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 (APTEDB) is also introduced as a TME-targeting ligand, yielding the TME-targeting nanomedicine, APTEDB-cyNP@CpG. APTEDB-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 APTEDB-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.

Affiliations

Ilkoo Noh  1 , Youngju Son  1 , Wonsik Jung  1 , Munsik Kim  2 , Dohyeon Kim  1 , Hocheol Shin  1 , Yeu-Chun Kim  2 , Sangyong Jon  3
1 Department of Biological Sciences, KAIST Institute for BioCentury, Korea Advanced Institute of Science and Technology (KAIST), 291 Daehak-ro, Daejeon, 34141, South Korea; Center for Precision Bio-Nanomedicine, Korea Advanced Institute of Science and Technology (KAIST), 291 Daehak-ro, Daejeon, 34141, South Korea.
2 Department of Chemical and Biomolecular Engineering, Korea Advanced Institute of Science and Technology (KAIST), 291 Daehak-ro, Daejeon, 34141, South Korea.
3 Department of Biological Sciences, KAIST Institute for BioCentury, Korea Advanced Institute of Science and Technology (KAIST), 291 Daehak-ro, Daejeon, 34141, South Korea; Center for Precision Bio-Nanomedicine, Korea Advanced Institute of Science and Technology (KAIST), 291 Daehak-ro, Daejeon, 34141, South Korea. Electronic address: syjon@kaist.ac.kr.