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Here, we propose an \u201cAlkaline\u2010Hammer\u201d strategy that combines pH modulation with alkaliptosis induction to overcome these obstacles. We engineered alkalizing sodium bicarbonate nanoparticles (JTC801\u2010NaHCO\n                    <jats:sub>3<\/jats:sub>\n                    @TPGS NPs) using a thin\u2010film hydration method. Upon delivery, these nanoparticles neutralize the acidic TME through sustained NaHCO\n                    <jats:sub>3<\/jats:sub>\n                    release, while JTC801, a selective opioid receptor\u2010like 1 (ORL1) antagonist, activates the NF\u2010\u03baB pathway to downregulate carbonic anhydrase IX (CA9). This dual action synergistically enhances intracellular alkalinization and induces alkaliptosis. Furthermore, we developed a laparoscopic intratumoral injection system to achieve precise delivery of JTC801\u2010NaHCO\n                    <jats:sub>3<\/jats:sub>\n                    @TPGS NPs in orthotopic pancreatic tumor models. This strategy increased CD8\n                    <jats:sup>+<\/jats:sup>\n                    T cells infiltration, reduced immunosuppressive populations (Tregs, MDSCs, and M2 macrophages), and elicited immunological memory, thereby converting immunologically \u201ccold\u201d tumors into \u201chot\u201d ones without evident systemic toxicity. These findings underscore the potential of localized alkaliptosis induction as a promising immunotherapeutic approach for pancreatic cancer.\n                  <\/jats:p>","DOI":"10.1002\/anie.8734845","type":"journal-article","created":{"date-parts":[[2026,7,15]],"date-time":"2026-07-15T11:47:08Z","timestamp":1784116028000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["\u201cAlkaline\u2010Hammer Strategy\u201d Breaks Acidic and Stromal Barriers to Induce Alkaliptosis and Enhance Immunotherapy in Pancreatic Cancer"],"prefix":"10.1002","volume":"65","author":[{"given":"Wei","family":"Liu","sequence":"first","affiliation":[{"name":"Department of Pancreatic and Biliary Surgery The First Affiliated Hospital of Harbin Medical University  Harbin Heilongjiang China"},{"name":"Key Laboratory of Hepatosplenic Surgery Ministry of Education The First Affiliated Hospital of Harbin Medical University  Harbin Heilongjiang 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