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The proper immune\u2010modulatory strategy to provoke a robust immune response is to simultaneously regulate T\u2010cell exhaustion and infiltration. Here, a new kind of carrier\u2010free nanoparticle is developed to simultaneously deliver chemotherapeutic drug (doxorubicin, DOX), cytolytic peptide (melittin, MPI), and anti\u2010TOX small interfering RNA (thymocyte selection\u2010associated high mobility group box protein, TOX) using a fluorinated prodrug strategy. In this way, the enhanced immunogenic cell death (ICD) induced by the combination of DOX and MPI can act as \u201coffense\u201d signaling to increase CD8<jats:sup>+<\/jats:sup> T\u2010cell infiltration, while the decreased TOX expression interfered with siTOX can serve as \u201cdefense\u201d signaling to mitigate CD8<jats:sup>+<\/jats:sup> T\u2010cell exhaustion. As a result, the integration of DOX, MPI, and siTOX in such a bifunctional system produced a potent antitumor immune response in liver cancer and metastasis, making it a promising delivery platform and effective strategy for converting \u201ccold\u201d tumors into \u201chot\u201d ones.<\/jats:p>","DOI":"10.1002\/adma.202203019","type":"journal-article","created":{"date-parts":[[2022,8,3]],"date-time":"2022-08-03T00:13:50Z","timestamp":1659485630000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":49,"title":["Manipulating Offense and Defense Signaling to Fight Cold Tumors with Carrier\u2010Free Nanoassembly of Fluorinated Prodrug and siRNA"],"prefix":"10.1002","volume":"34","author":[{"given":"Pengkai","family":"Wu","sequence":"first","affiliation":[{"name":"Department of Hepatobiliary Surgery Nanjing Drum Tower Hospital The Affiliated Hospital of Nanjing University Medical School  Nanjing Jiangsu Province 210008 P.R. 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