Metronomic Mild-Temperature Photothermal Therapy Modulating Tumor-Associated Macrophage Repolarization as a Neoadjuvant Immunotherapy

Neoadjuvant immunotherapy is superior to adjuvant immunotherapy in terms of immune suppression relief and antitumor immunity activation but inevitably suffers from immune-related toxicities. To minimize the toxic side effects, a local metronomic mild-temperature photothermal therapy (PTT) is proposed herein as a neoadjuvant immunotherapy. It was disclosed that the Prussian blue nanoparticle (PBNP)-mediated metronomic mild-temperature PTT effectively inhibited the growth of both primary and distal tumors on 4T1 xenograft tumor-bearing mice by effectively reversing the immunoimpressive TME through repolarizing M2-like TAMs to tumoricidal M1-like ones. Synergistically, the reprogrammed M1-like phenotype upregulated the percentage of cytotoxic T lymphocytes in the spleen and tumor, leading to an activated systemic immunity. This together with the demonstrated biosafety underscores the great potential of PBNP-mediated metronomic mild-temperature PTT as immunotherapy for reducing tumor burden presurgery and preventing tumor reoccurrence and metastasis postsurgery with minimized side toxic effects.