Tumor-associated Macrophage Membrane-Camouflaged Ph-Responsive Polymeric Micelles for Combined Cancer Chemotherapy-Sensitized Immunotherapy.

The low immunogenicity and tumor immunosuppressive microenvironment (TIM) are two major obstacles for cancer immunotherapy. Synergistically immunogenic cell death induction and tumor-associated macrophages depletion could perfectly overcome this limitation. Herein, a tumor-associated macrophage (TAMs) membrane-camouflaged pH-responsive doxorubicin (DOX) loaded hyaluronic acid (HA)-g-poly (histidine) polymeric micelles (DHP@M2) was fabricated for the first time. DHP@M2 could effectively accumulated into tumor regions via TAMs membrane mediated immune camouflage. In acidic tumor microenvironment, particle size of DHP was enlarged due to decrease hydrophobic interaction of inner core, which caused a "membrane escape effect" to expose inner HA residue. Together high expression of α4β1 integrin, DHP@M2 could reach CD44/VCAM-1 dual-targetability to facilitate intracellular DOX accumulation for efficient ICD induction. Meanwhile, TAMs membrane could absorb colony stimulating factor 1(CSF1) through high expression of its receptor (CSF1R) on TAMs membrane to deplete TAMs in tumor tissues and relieved TIM. This strategy could efficiently induce cytotoxic T lymphocyte (CTLs) infiltration for antitumor immune response and inhibit tumor progression in 4T1 tumor bearing Balb/c mice. Therefore, DHP@M2 is suitable for cancer chemotherapy-sensitized immunotherapy.