Membrane-Coated Hollow Manganese Nitrogen Carbon Nanocomposites Synergize Phototherapy and STING Activation for Immunogenic Tumor Microenvironment Remodeling

Cancer remains a leading global cause of death, with conventional therapies often limited. While immune therapy has revolutionized cancer therapy with the use of immune agents, its efficacy is often curtailed by the immunosuppressive tumor microenvironment (TME). To address the limited effectiveness of existing immunotherapies, we developed a multifunctional biomimetic nanocomposite, tumor cell membrane-coated hollow manganese nitrogen carbon nanocomposite (HMn-NC@M), integrating phototherapy and immunotherapy. HMn-NC@M enhances tumor targeting and performs photothermal and photodynamic therapy under near-infrared light, inducing immunogenic cell death (ICD), releasing tumor antigens and damage-associated molecular patterns (DAMPs). This triggers antitumor immune responses while modulating the tumor microenvironment by decomposing hydrogen peroxide, alleviating hypoxia, depleting glutathione, and releasing Mn²⁺ ions. Mn²⁺ activates the cGAS-STING pathway, amplifying ICD-induced immunity, promoting dendritic cell maturation, and enhancing cytotoxic <i>T lymphocyte</i> infiltration. Transcriptome profiling of <i>in vitro</i> models unveiled the activation of key pathways governing tumor proliferation, apoptosis, and immune modulation. Evaluation of <i>in vivo</i> models demonstrated tumor suppression of 44% with monotherapy and 92% with the combination of phototherapy and immunotherapy, highlighting the potential of HMn-NC@M as a multifunctional nanotherapeutic platform for cancer therapy.