Focused ultrasound-triggered doxorubicin liposomes reshape tumor microenvironment to boost checkpoint depletion in triple-negative breast cancer model.

High Intensity Focused Ultrasound (HiFUS) combined with cavitation-responsive liposomes (IMP301) offers a therapeutic strategy to enhance immunotherapy efficacy in triple-negative breast cancer (TNBC). This study investigates how HIFUS, a non-invasive modality, remodels the tumor microenvironment (TME), transforming "suppressive" tumors into "responsive" ones and improving susceptibility to immune checkpoint blockade (ICB). We show that HIFUS increases vascular permeability and induces immunogenic cell death (ICD), enabling localized release of doxorubicin (Dox) from IMP301. In preclinical models, treatment improved immune infiltration, with elevated NK cells, CD8 T cells, and M1 macrophages, and reduced myeloid-derived suppressor cells (MDSCs). Antigen-specific T cells increased ∼3.1-fold (p < 0.0001), and long-lasting memory T cells prevented metastasis and recurrence. Notably, targeted Dox delivery minimized systemic toxicity, permitting higher dosing with fewer adverse effects. In tumor growth studies, the combination of HIFUS and IMP301 with anti-PD1 achieved complete remission, highlighting potential for durable cancer control. Specifically, remission occurred in 4 of 10 mice, with survival extended to 50 vs 26 days (p < 0.0001). These findings demonstrate that integrating HiFUS with IMP301 effectively modulates the TME and enhances checkpoint blockade therapy, supporting its translational potential in TNBC and other solid tumors.