Tri-Modal Sacc Synergistic Therapy Via Homotypic-Targeting Multifunctional Nanomaterials

Salivary adenoid cystic carcinoma (SACC) is classified as an immune-desert "cold tumor" due to its high heterogeneity, low tumor-infiltrating lymphocytes, and PD-L1 negativity, with a postoperative local recurrence rate of 40%-60%. Conventional treatments struggle to control metastases, necessitating novel therapeutic strategies. This study aims to develop a homotypic targeting multifunctional nanomaterial coated with tumor cell membranes to reshape the SACC immune microenvironment and activate systemic antitumor immunity via photothermal therapy (PTT), photodynamic therapy (PDT), and chemodynamic therapy (CDT). Layer-by-layer self-assembly was used to prepare mesoporous silica nanoparticles loaded with Fe₃O₄/MnO₂ and IR780, coated with SACC cell membranes to form MFMIMON NPs. Their Fenton activity and peroxidase-like properties were assessed in a simulated tumor environment. Cytotoxicity and proliferation inhibition against ACC-LM cells were evaluated via CCK8, Calcein-AM/PI staining, and colony formation assays. A subcutaneous SACC tumor model was established to analyze tumor suppression and immune response under near-infrared (NIR) laser irradiation. MFMIMON NPs accumulated efficiently at tumor sites, inducing mitochondrial membrane potential collapse and lipid peroxidation upon NIR laser exposure, leading to tumor cell death. Their catalytic activity significantly enhanced oxidative stress and induced immunogenic cell death (ICD). In vivo studies demonstrated that MFMIMON NPs, combined with NIR laser, suppressed tumor growth and activated systemic antitumor immunity. MFMIMON NPs effectively overcame the immunosuppressive SACC microenvironment through homotypic targeting and tri-modal therapy, inducing ICD and activating antitumor immunity, providing a theoretical basis for clinical translation.