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Directly removing CAFs may prove ineffective and even promote tumor metastasis. To address this challenge, a sequential nanocomposite hydrogel that reshapes CAF behavior is developed, enhancing tumor\u2010infiltrating T\u2010cells in osteosarcoma. The approach utilizes an injectable blend of carboxymethyl chitosan and tetrabasic polyethylene glycol, forming a hydrogel for controlled release of a potent CAF suppressor (Nox4 inhibitor, Nox4\n                    <jats:italic>i<\/jats:italic>\n                    ) and liposomal Doxorubicin (L\u2010Dox) to induce immunogenic cell death (ICD) upon in situ administration. Nox4\n                    <jats:italic>i<\/jats:italic>\n                    effectively counters CAF activation, overcoming T\u2010cell exclusion mechanisms, followed by programmed L\u2010Dox release for ICD induction in stroma\u2010rich osteosarcoma models. Combining the co\u2010delivery gel with \u03b1PD\u20101 checkpoint inhibitor further enhances its effectiveness in an orthotopic osteosarcoma model. Immunophenotyping data underscore a significant boost in tumor T\u2010cell infiltration and favorable anti\u2010tumor immunity at the whole\u2010animal level.\n                  <\/jats:p>","DOI":"10.1002\/adma.202309591","type":"journal-article","created":{"date-parts":[[2023,12,19]],"date-time":"2023-12-19T18:37:00Z","timestamp":1703011020000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":58,"title":["Synergistic Chemoimmunotherapy Augmentation via Sequential Nanocomposite Hydrogel\u2010Mediated Reprogramming of Cancer\u2010Associated Fibroblasts in Osteosarcoma"],"prefix":"10.1002","volume":"36","author":[{"given":"Hui","family":"Wang","sequence":"first","affiliation":[{"name":"School of Medical Technology Beijing Institute of Technology  Beijing 100081 China"},{"name":"CAS Key Laboratory for Biomedical Effects of Nanomaterials and Nanosafety and CAS Center for Excellence in Nanoscience National Center for Nanoscience and 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