Fever-Inducible Lipid Nanocomposite for Boosting Cancer Therapy through Synergistic Engineering of a Tumor Microenvironment

A fever-mimic response capable of recruiting reprogrammed macrophages holds great potential in the engineering of the tumor microenvironment (TME). Low-temperature photothermal therapy (LT-PTT) can maintain tumors at a fever-like temperature (<45 °C) temporarily; however, it still faces several challenges in efficient regulation of TME because of reciprocal cross-talk between the bypass pathways. Here, we report a synergistic engineering of TME through an enhanced activation of a fever-mimic response based on both LT-PTT and tumor vascular normalization. Such engineering is achieved by a fever-inducible lipid nanocomposite (GNR-T/CM-L), which produces mild heat (∼43 °C) and sequentially releases multicomponents to cooperatively upregulate interferon-gamma under NIR irradiation, forming a bidirectionally closed loop for downstream M1 tumor-associated macrophage polarization and promoting the inhibition of the tumor growth. In proof-of-concept studies, GNR-T/CM-L demonstrated efficient tumor ablation in breast tumor xenograft-bearing mice and significantly prolonged their survival period. It paves an avenue to precisely reprogram TME for efficient cancer therapy through synergistic pathways of creating fever-like responses in the tumor.