Targeting the SOX9/TIMP1 Axis with iRGD‐Conjugated Nanoplatform Enhances Dendritic Cell Function and Photodynamic Immunotherapy in Gastric Cancer

Abstract Gastric cancer (GC) remains a therapeutic challenge due to its immunosuppressive microenvironment. This study reveals that the SOX9/TIMP1/FAK/PI3K axis impedes dendritic cell (DC) maturation and antitumor immunity in GC, using integrated single‐cell RNA sequencing (scRNA‐seq) and spatial transcriptomics (ST‐seq) analysis. Irgd‐conjugated poly(lactic‐co‐glycolic acid) (PLGA) nanoparticles (NPs) co‐loaded with small interfering RNA targeting SOX9 (si‐SOX9), the photosensitizer chlorin e6 (Ce6), and L‐arginine (L‐Arg) (termed iRGD NPs@si‐SOX9/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‐infrared (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⁺ T‐cell activation. In vivo, iRGD modification boosts tumor accumulation of NPs, and NP‐mediated PDT synergized with SOX9 silencing to suppress tumor growth in GC xenografts. Mechanistically, NPs@si‐SOX9/CL blocks SOX9‐driven transcriptional activation of TIMP1, reversing FAK/PI3K signaling and restoring DC function. Consequently, tumor‐infiltrating 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‐intrinsic immunosuppression and potentiating PDT efficacy.