Cancer immunotherapy has improved the survival rate of patients with malignant tumors. However, the response of solid tumors to immunotherapy is quite limited. Here, we report a pH-responsive nanocomposite for augmented sonodynamic-chemodynamic immunotherapy. This Mn-CaCO 3 -2,2′-azobis[2-(2-imidazolin-2-yl) propane]-dihydrochloride (AIPH) nanosystem, Lipo@MCA, was prepared through a simple two-step reaction. It released sonosensitizer AIPH and Ca 2+ within the acidic tumor microenvironment. AIPH generated alkyl free radicals under ultrasound irradiation, and Mn 2+ produces ·OH through Fenton-like reaction. The Ca 2+ induced calcium overload in tumor cells. This induced mitochondrial dysfunction and promoted tumor cell apoptosis. Lipo@MCA also inhibited the phosphorylation of Akt and PI3K. In vitro experiments indicated that the nanoparticle inhibited tumor cell invasion and migration, and induced tumor cell apoptosis. In vivo experiments demonstrated that Lipo@MCA inhibited tumor growth by promoting cytokine secretion, stimulating dendritic cell maturation, and enhancing T-cell differentiation. In summary, this study paves the way for synergistic inhibition of tumor cell metastasis and immunotherapy in solid tumors through PI3K signaling pathway inhibition.
Cuixia Zheng,Qingling Song,Hongjuan Zhao,Yueyue Kong,Lingling Sun,Xinxin Liu,Qianhua Feng,Lei Wang
The failure of any phase in continuous multi-link immune response process can cause unsatisfactory outcomes, which might be improved by all-cancer-immunity-cycle boosted strategy. Herein, a nanoplatform Mn/CaCO 3 @PL/SLC is developed, which is based on palmitoyl ascorbate (PA)-liposome (PL) loaded with Mn-doped CaCO 3 nanoparticles (Mn/CaCO 3 NPs) and carbonic anhydrase (CAIX) inhibitor SLC-0111. The nanoplatform comprehensively amplifies all immune stages including tumor-associated antigens (TAAs) release and presentation, T cells activation and infiltration , as well as tumor cells destruction. In detail, Mn-triggered lipid peroxidation facilitates TAAs release and subsequent T cells activation to initiate immunity cycle. Additionally, SLC-0111 and PA amplify the infiltration and tumor killing activity of these effector T cells. The former polarizes the immunosuppressive tumor microenvironment to an immune-active phenotype and the latter enhances the function of tumor-infiltrating T lymphocytes. Importantly, Mn augments the all-immunity-cycle by promoting cGAS-STING pathway activation. In summary, the Mn/CaCO 3 @PL/SLC nanoplatform is verified to boost anti-tumor immunity and achieve outstanding immunotherapeutic effects in eradicating tumor and preventing tumor metastasis. Such an all-cancer-immunity-cycle boosted strategy is meaningful for antitumor immunotherapy .
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