Heat-Confined Tumor-Docking Reversible Thermogel Potentiates Systemic Antitumor Immune Response During Near-Infrared Photothermal Ablation in Triple-Negative Breast Cancer

Triple-negative breast cancer (TNBC) features immunologically cold tumor microenvironments with limited cytotoxic T lymphocyte (CTL) infiltration. Although ablation therapies have demonstrated modulation of cold TNBC tumors to inflamed hot tumors, recruitment of myeloid derived suppressor cells (MDSCs) at the tumors post ablation therapies prevents the infiltration of CTLs and challenge the antitumor potentials of T-cell therapies. Here, a thermal ablation immunotherapy strategy is developed to prevent the immune suppressive effects of MDSCs during photothermal ablation and induce a durable systemic antitumor immunity to eradicate TNBC tumors. An injectable pluronic F127/hyaluronic acid (HA)-based hydrogel embedded with manganese dioxide (BM) nanoparticles and TLR7 agonist resiquimod (R848) (BAGEL-R848), is synthesized to induce in situ laser-assisted gelation of the hydrogel and achieve desired ablation temperatures at a low laser-exposure time. Upon 808-nm laser irradiation, a significant reduction in the tumor burden is observed in BAGEL-R848-injected 4T1 tumor-bearing mice. The ablation induced immunogenic cell death and sustained release of R848 from BAGEL-R848 promotes dendritic cell maturation and reduced MDSCs localization in tumors. In addition, inflammatory M1 macrophages and CD8+IFN+ CTL are enriched in distant tumors in bilateral 4T1 tumor model, preventing metastatic tumor growth and signifying the potential of BAGEL-R848 to treat TNBC.

Automated summary

A thermal ablation immunotherapy strategy was developed to prevent the immune suppressive effects of myeloid derived suppressor cells during photothermal ablation, inducing a durable systemic antitumor immunity to eradicate TNBC tumors. The injectable hydrogel BAGEL-R848 showed promising results in reducing tumor burden, promoting dendritic cell maturation, and enriching inflammatory M1 macrophages and CD8+IFN+ CTL to prevent metastatic tumor growth in a bilateral 4T1 tumor model.