Enhanced Tumor Immunotherapy by Triple Amplification Effects of Nanomedicine on the STING Signaling Pathway in Dendritic Cells

Abstract Insufficient activation of stimulator of interferon genes (STING) signaling pathway in tumor‐associated dendritic cells limits the efficiency of tumor immunotherapy. Herein, the “three‐in‐one” IAHA‐LaP/siPTPN6 NPs containing lanthanum ions (La 3+ ), cGAMP, and PTPN6 siRNA are developed for triple amplification of the STING pathway. In vitro results demonstrate that La 3+ significantly promotes cGAMP‐mediated activation of the STING pathway by enhancing the phosphorylation of STING, TBK1, IRF3, and NF‐ κ B p65. Moreover, the IAHA‐LaP/siPTPN6 NPs further significantly enhance the phosphorylation of STING and NF‐ κ B p65 and augment K63‐linked ubiquitination of STING protein via siPTPN6‐mediated downregulation of SHP‐1 protein. Furthermore, NPs improve the secretion of IFN β (2.4‐fold), IL‐6 (1.5‐fold), and TNF‐ α (1.4‐fold), thereby promoting DCs maturation compared to the mixture of La 3+ and cGAMP. In vivo results show that the IAHA‐LaP/siPTPN6 NPs remarkably inhibit primary tumor growth by increasing the percentage of mature DCs in tumor‐draining lymph nodes, polarizing M2/M1 phenotype in TME, and promoting the infiltration of CD8 + T cells into tumors. Moreover, these NPs dramatically prevent the growth of distal tumor by inducing systemic anti‐tumor immunity and generating a long‐term anti‐tumor memory for protection against tumor recurrence in mice bearing bilateral B16F10. These IAHA‐LaP/siPTPN6 NPs may offer a promising platform for robust anti‐tumor immune responses.