A stimuli-responsive immunostimulant to activate chemo-immunotherapeutic effects by inducing DNA damage and STING activation.

The integration of chemotherapy with systemic immune activation represents a promising approach to eradicate metastatic tumors. In this study, a stimuli-responsive immunostimulant nanoplatform (denoted as MV@Lip) was developed to synergistically activate antitumor immunity via chemotherapy-induced DNA damage and subsequent activation of the stimulator of interferon genes (STING) signaling pathway. The MV@Lip system encapsulates the chemotherapeutic agent mitoxantrone (Mit) and the STING agonist vadimezan (Vad) within a redox-responsive liposomal carrier. MV@Lip was indicated to enhance drug stability, while simultaneously promoting efficient co-delivery of both agents into tumor cells and suppressing tumor proliferation. Mechanistically, MV@Lip exerts its therapeutic efficacy through inducing DNA damage and triggering immunogenic cell death (ICD) to enhance tumor immunogenicity by releasing damage-associated molecular patterns (DAMPs). Concurrently, the released Vadimezan could activate the STING pathway, amplifying innate immune responses through the production of proinflammatory factors and the recruitment of immune effector cells. This concerted action facilitates the infiltration and activation of natural killer (NK) cells and T lymphocytes in the tumor microenvironment, ultimately leading to the suppression of both primary and metastatic tumors. These findings provide a compelling basis for advancing chemotherapeutic combinations as immune-stimulating strategies in the treatment of metastatic malignancies.