A bispecific nanomodulator to potentiate photothermal cancer immunotherapy

Photothermal therapy (PTT) has shown great potential in cancer treatment for inducing photothermal ablation and eliciting immune responses. However, PTT-triggered antitumor immunity is severely hampered by the dynamic amplification of programmed cell death protein ligand 1(PD-L1) and indoleamine 2, 3-dioxygenase 1(IDO-1) in tumors. To thoroughly liberate PTT efficiency, a bispecific nanomodulator is developed to trigger PTT and dual-block PD-L1 and IDO-1 pathways for boosting effective antitumor immunity. The nanomodulator is excipient-free and self-assembled by leveraging hydrophobic interactions among indocyanine green (ICG), JQ1 and BMS986205 (BMS). The loading efficiency of JQ1 and BMS is as high as 42.0% and 51.8% at a feeding ratio of 1:1. The bispecific nanomodulator efficiently induces PTT and immunogenic cell death (ICD) upon laser irradiation. Moreover, PTT-mediated upregulation of PD-L1 and IDO-1 activation are reversed by the nanomodulator, leading to enhanced infiltration of CD8 + T cells and high levels of TNF-α and IFN-γ in tumors. The bispecific nanomodulator significantly inhibits the growth and metastasis of subcutaneous tumors in mice, and provides defensive effects against tumor rechallenge through immune memory effects. Overall, the bispecific nanomodulator provides a feasible and safe approach for potentiating photothermal immunotherapy against solid tumors. • A bispecific nanomodulator to potentiate PTT-triggered antitumor immunity via dual-blocking PD-L1 and IDO-1 pathways. • The nanomodulator is excipient-free and self-assembled via hydrophobic interactions among small molecules. • The nanomodulator inhibits tumor growth and metastasis, and stimulates immune memory effects preventing tumor recurrence.