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

Abstract

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.

Research Progress of Nanomedicine-Based Mild Photothermal Therapy in Tumor

“… 219 , 220 Additionally, the slight increase of local temperature of tumor can lead to a switch in the phenotype of tumor-associated macrophages (TAMs) from an M2 immunosuppressive phenotype to an M1 immunosensitive phenotype, and inhibit immunosuppressive regulatory T cells (Tregs). 221 , 222 All in all, mPTT generates an overall immune-promoting microenvironment from multiple pathways, acting as possibly the best candidate for adjuvant immunotherapy.…”

Targeted Nanophotoimmunotherapy Potentiates Cancer Treatment by Enhancing Tumor Immunogenicity and Improving the Immunosuppressive Tumor Microenvironment

“…107−109 The combination of PTT with sodium tanshinone IIA sulfonate (for TVN) enabled TME reengineering. 72 Nitric oxide (NO) is an important signaling molecule that regulates human life activities and induces the expression of endogenous angiogenic factors such as vascular endothelial growth factor and fibroblast growth factor. Nano-PIT could normalize tumor vasculature, alleviate hypoxia, and reprogram the immunosuppressed TME by coencapsulating NO donors and photothermal agents (Figure 6A).…”

“…Tumor vascular normalization (TVN) can repair damaged tumor vessels, promote immune cell infiltration, and reduce the signaling of tumor metastasis . TVN improves ITM and reduces hypoxia at the tumor site, resulting in immune checkpoint down-regulation, cytokines and immunosuppressive cells decrease. − The combination of PTT with sodium tanshinone IIA sulfonate (for TVN) enabled TME reengineering . Nitric oxide (NO) is an important signaling molecule that regulates human life activities and induces the expression of endogenous angiogenic factors such as vascular endothelial growth factor and fibroblast growth factor.…”

Combined cancer therapeutics—Tackling the complexity of the tumor microenvironment

“…Chemotherapeutic agents, such as doxorubicin, cisplatin or paclitaxel, are frequently attached or adsorbed to the coating layer to enhance the therapeutic effect of the nanoformulation. External stimuli, such as light, ultrasound or magnetic field enhance the release of coating layer and the solubilization of the materials from the core Oil-droplets PFOB@IMHNPs Hypoxia PDT, PTT (Kv et al, 2020) α-CD/PEG-4000 hydrogel GEL-CpG NP-DOX TAM's, T lymphocytes Chemotherapy, Immunotherapy (Dong et al, 2020) Lipid nanocomposite GNR-T/CM-L TAM's Chemotherapy, LT-PTT (Qu et al, 2020) Zeolitic imidazolate…”