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-alpha and IFN-gamma 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.(c) 2022 Elsevier Ltd. All rights reserved.