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However, precise modulation of the tumor microenvironment using manganese ions remains a challenge. Dopamine, with its controlled release properties within the tumor microenvironment, offers significant potential for precision drug delivery systems. Metastatic renal cell carcinoma (RCC), being refractory to conventional treatments, necessitates innovative therapeutic approaches. In this study, a multifunctional manganese\u2010polydopamine nano\u2010immunomodulator coated with hyaluronic acid (PDA\u2010Mn\u2010HA NPs) is developed. These nanoparticles selectively bind to CD44 molecules, which are highly expressed in tumor\u2010associated macrophages and RCC cells, and release manganese ions in a tumor microenvironment\u2010responsive manner. Treatment with PDA\u2010Mn\u2010HA NPs effectively induces macrophage M1 polarization, triggers the production of pro\u2010inflammatory cytokines and chemokines. Transcriptomic analysis reveals that PDA\u2010Mn\u2010HA NPs polarize and activate macrophages through the reactive oxygen species(ROS)\u2010STING\u2010p38\/MAPK signaling pathway. Additionally, PDA\u2010Mn\u2010HA NPs induce ROS\u2010caspase\u20103\/GSDME\u2010dependent pyroptosis in RCC cells via a Fenton\u2010like reaction. In RCC mouse models, PDA\u2010Mn\u2010HA NPs remodel the macrophage\u2010mediated immune microenvironment, enhance immune cell infiltration, and significantly suppress tumor growth. In conclusion, multifunctional PDA\u2010Mn\u2010HA NPs demonstrate translational potential by addressing the limitations of precision manganese delivery and achieving synergistic targeting of macrophages and tumor cells, offering a promising therapeutic strategy for RCC.<\/jats:p>","DOI":"10.1002\/adhm.202500141","type":"journal-article","created":{"date-parts":[[2025,5,21]],"date-time":"2025-05-21T01:59:04Z","timestamp":1747792744000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":17,"title":["Synergistic Provoking of Pyroptosis and STING Pathway by Multifunctional Manganese\u2010Polydopamine Nano\u2010Immunomodulator for Enhanced Renal Cell Carcinoma Immunotherapy"],"prefix":"10.1002","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7933-7439","authenticated-orcid":false,"given":"Yufei","family":"Du","sequence":"first","affiliation":[{"name":"Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics 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