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This study reveals that the SOX9\/TIMP1\/FAK\/PI3K axis impedes dendritic cell (DC) maturation and antitumor immunity in GC, using integrated single\u2010cell RNA sequencing (scRNA\u2010seq) and spatial transcriptomics (ST\u2010seq) analysis. Irgd\u2010conjugated poly(lactic\u2010co\u2010glycolic acid) (PLGA) nanoparticles (NPs) co\u2010loaded with small interfering RNA targeting SOX9 (si\u2010SOX9), the photosensitizer chlorin e6 (Ce6), and L\u2010arginine (L\u2010Arg) (termed iRGD NPs@si\u2010SOX9\/CL) are developed to simultaneously disrupt this immunosuppressive axis and amplify photodynamic therapy (PDT). In vitro, these NPs enhance cellular uptake and lysosomal escape, suppressing SOX9 expression and generating reactive oxygen species (ROS) and nitric oxide (NO) upon near\u2010infrared (NIR) irradiation. This dual action significantly inhibits GC cell proliferation, migration, and invasion while promoting DC maturation (evidenced by elevated CD80\/CD86 expression) and CD8\u207a T\u2010cell activation.\u00a0In vivo, iRGD modification boosts tumor accumulation of NPs, and NP\u2010mediated PDT synergized with SOX9 silencing to suppress tumor growth in GC xenografts. Mechanistically, NPs@si\u2010SOX9\/CL blocks SOX9\u2010driven transcriptional activation of TIMP1, reversing FAK\/PI3K signaling and restoring DC function. Consequently, tumor\u2010infiltrating mature DCs and cytotoxic T lymphocytes increase significantly, reshaping the immunosuppressive niche. This nanoplatform offers a promising strategy to augment GC immunotherapy by precisely targeting tumor\u2010intrinsic immunosuppression and potentiating PDT efficacy.<\/jats:p>","DOI":"10.1002\/advs.202510500","type":"journal-article","created":{"date-parts":[[2025,11,21]],"date-time":"2025-11-21T19:36:46Z","timestamp":1763753806000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Targeting the SOX9\/TIMP1 Axis with iRGD\u2010Conjugated Nanoplatform Enhances Dendritic Cell Function and Photodynamic Immunotherapy in Gastric Cancer"],"prefix":"10.1002","volume":"13","author":[{"given":"Banghua","family":"Zhong","sequence":"first","affiliation":[{"name":"Department of Gastrointestinal Surgery The First Hospital of China Medical University  Shenyang 110001 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yijie","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of 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