pH and ROS Dual‐Responsive Autocatalytic Release System Potentiates Immunotherapy of Colorectal Cancer

Abstract The immunosuppressive microenvironment severely limits the responsiveness of colorectal cancer (CRC) to immunotherapy. Herein, a pH and reactive oxygen species (ROS) dual‐responsive autocatalytic release system (TPDM/PGA) is constructed to reverse the immunosuppressive microenvironment and potentiate CRC immunotherapy. Dihydroartemisinin (DHA) and mitoxantrone (MTO) are conjugated to ROS‐responsive polyethylenimine (TP) via a ROS‐cleavable linker, respectively, and then coated with polyglutamic acid (PGA) to endow pH and ROS dual‐responsiveness. The dissociation of PGA within the acidic TME facilitates its deep penetration and cell internalization, while the intracellular released DHA and MTO in response to high levels of H 2 O 2 further produced a large amount of ROS, forming positive feedback to accelerate drug release and exacerbate oxidative stress. TPDM/PGA collaboratively reversed the immunosuppressive microenvironment and induced a strong anti‐tumor immune response when combined with anti‐PD‐L1 antibody, significantly inhibiting tumor growth and prolonging the survival time of CT26 and MC38 tumor‐bearing mice. The excellent therapeutic effect, together with the good tolerance, make TPDM/PGA a promising candidate for enhanced immunotherapy of colorectal cancer.