Hydrotalcites-Induced Pyroptosis Combined with Toll-Like Receptor Activation Elicited Dual Stimulation of Innate and Adaptive Immunity

Increasing evidence illustrates the significance of promoting tumor immunogenicity and an efficient immune response in immunotherapy, but the immunosuppressive tumor microenvironment (TME) remains an obstacle. Herein, AlZn hydrotalcite (AZOH) was synthesized as a pyroptosis inducer and further loaded with R848 to formulate R@AZOH. R@AZOH efficiently triggered CT26 cell pyroptosis through Zn²⁺ overload-evoked mitochondrial dysfunction and its downstream caspase-1/GSDMD pathway, resulting in the release of inflammatory cytokines, membrane fracture, and immunogenic cell death (ICD). Moreover, R@AZOH served as antigen traps to facilitate antigen presentation, thereby cooperating with TLR activation to dually stimulate dendritic cells (DCs). The combination of R@AZOH rapidly initiated innate immunity and prolonged the adaptive immune response, resulting in the suppression of tumor growth, immune cell activation and a "hot" tumor niche. The potent antitumor immunity was further enhanced by combination with an immune checkpoint inhibitor (αCTLA-4), which inhibited both primary and distant tumors, as well as systemic immune activation. Astonishingly, we also explored the potential application of R@AZOH as a tumor vaccine adjuvant and demonstrated its ability to elicit immunological memory to prevent tumor growth in an orthotopic melanoma model. Overall, our work emphasized the potential application of combining pyroptosis and TLR activation to stimulate both innate and adaptive immunity to overcome the immunosuppressive TME and presented a good adjuvant candidate.