Amplifying cancer chemoimmunotherapy through F4/80+CD11c+ DC-like macrophages induced by micellar docetaxel together with a TLR7/8 nanoagonist

Chemotherapy-based combinational immunomodulation has been developed to inflame the “cold” tumor immune microenvironment (TiME) for enhanced triple-negative breast cancer (TNBC) chemoimmunotherapy. However, the potential of docetaxel-based chemotherapy combined with immunomodulation by TLR7/8 agonists remains undiscovered. Herein, we first constructed micellar docetaxel (DTX-m) and a TLR7/8 nanoagonist suitable for systematic administration, R848 nanoparticles (R848 NPs). By adjusting the administration sequence, the combination of DTX-m and R848 NPs can efficiently inhibit tumor growth in vivo in a rodent triple-negative breast cancer model. The results of a mechanistic study reveal that alternate sequential administration promotes the polarization of macrophages to F4/80+CD11c+ DC-like macrophages and cumulatively promotes the secretion of CXCL10 and proinflammatory cytokines, which boost the recruitment of NK cells and APCs to reinflame the tumor immune microenvironment, further facilitating the recruitment and proliferation of effector T cells and amplifying tumor chemoimmunotherapy. Administration sequence regulates the therapeutic outcome by steering the polarization of macrophage phenotypes.