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Herein, the \u201cthree\u2010in\u2010one\u201d IAHA\u2010LaP\/siPTPN6 NPs containing lanthanum ions (La<jats:sup>3+<\/jats:sup>), cGAMP, and PTPN6 siRNA are developed for triple amplification of the STING pathway. In vitro results demonstrate that La<jats:sup>3+<\/jats:sup> significantly promotes cGAMP\u2010mediated activation of the STING pathway by enhancing the phosphorylation of STING, TBK1, IRF3, and NF\u2010<jats:italic>\u03ba<\/jats:italic>B p65. Moreover, the IAHA\u2010LaP\/siPTPN6 NPs further significantly enhance the phosphorylation of STING and NF\u2010<jats:italic>\u03ba<\/jats:italic>B p65 and augment K63\u2010linked ubiquitination of STING protein via siPTPN6\u2010mediated downregulation of SHP\u20101 protein. Furthermore, NPs improve the secretion of IFN<jats:italic>\u03b2<\/jats:italic> (2.4\u2010fold), IL\u20106 (1.5\u2010fold), and TNF\u2010<jats:italic>\u03b1<\/jats:italic> (1.4\u2010fold), thereby promoting DCs maturation compared to the mixture of La<jats:sup>3+<\/jats:sup> and cGAMP. In vivo results show that the IAHA\u2010LaP\/siPTPN6 NPs remarkably inhibit primary tumor growth by increasing the percentage of mature DCs in tumor\u2010draining lymph nodes, polarizing M2\/M1 phenotype in TME, and promoting the infiltration of CD8<jats:sup>+<\/jats:sup>T cells into tumors. Moreover, these NPs dramatically prevent the growth of distal tumor by inducing systemic anti\u2010tumor immunity and generating a long\u2010term anti\u2010tumor memory for protection against tumor recurrence in mice bearing bilateral B16F10. These IAHA\u2010LaP\/siPTPN6 NPs may offer a promising platform for robust anti\u2010tumor immune responses.<\/jats:p>","DOI":"10.1002\/adhm.202403143","type":"journal-article","created":{"date-parts":[[2024,10,23]],"date-time":"2024-10-23T06:07:07Z","timestamp":1729663627000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["Enhanced Tumor Immunotherapy by Triple Amplification Effects of Nanomedicine on the STING Signaling Pathway in Dendritic Cells"],"prefix":"10.1002","volume":"14","author":[{"given":"Xiang\u2010Yu","family":"Wang","sequence":"first","affiliation":[{"name":"Beijing Key Laboratory of Molecular Pharmaceutics and New Drug Delivery Systems State Key Laboratory of Natural and Biomimetic Drugs School of Pharmaceutical Sciences Peking University  Beijing 100191 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