Tumor microenvironment responsive polymer nano-immunomodulators for precise immunotherapy of hepatocellular carcinoma

The combination of photodynamic therapy and immunotherapy has emerged as a safe and effective cancer treatment strategy. However, traditional photodynamic therapy and precision anti-tumor immunotherapy still face challenges, such as weak light source penetration, poor targeting specificity, low response rates and immune-related adverse effects. Herein, a smart polymer nano-immunomodulator (SPNI) that can respond to the tumor microenvironment for precise photodynamic immunotherapy of cancer is reported. This SPNI is self-assembled from pH and glutathione (GSH) bi-responsive amphiphilic polymers, simultaneously loaded with photosensitive materials and oxygen-carrying molecules, subsequently is wrapped by hepatocellular carcinoma (HCC) cell membrane using a simple coextrusion method to generate biomimetic nanoparticles. Upon reaching the tumor site, the SPNI degrades in the tumor microenvironment, effectively releasing photosensitive substances with chemophotodynamic effects to directly eliminate tumors without an external light source. Additionally, the immunosuppressant blocks PD-1/PD-L1 signaling pathways to enhance the body’s endogenous anti-tumor immune response, inhibiting tumor growth and metastasis. Furthermore, the incorporated immunosuppressant effectively blocks PD-1/PD-L1 signaling pathways, thereby potentiating endogenous anti-tumor immune responses to suppress both primary tumor growth and metastatic progression. This innovative combination of tumor microenvironment-responsive photodynamic therapy and checkpoint blockade immunotherapy demonstrates remarkable efficacy in anti-HCC treatment and shows substantial potential for clinical translation. The SPNI platform represents a significant advancement in precision cancer therapy by simultaneously addressing multiple limitations of current treatment modalities.