Abstract
Recurrence and metastasis remain significant challenges in the clinical treatment of hepatocellular carcinoma (HCC). The integration of photodynamic therapy and immunotherapy has emerged as a promising strategy for treating cancer in terms of safety and efficacy. However, conventional photodynamic therapy and anti-tumor immunotherapy face several limitations, including inadequate light source penetration, poor targeting precision, low response rates, and immune-related adverse effects. To address these issues, we developed a tumor microenvironment responsive polymer nano-immunomodulator for precise photodynamic immunotherapy of HCC. The nano-immunomodulator is self-assembled from glutathione responsive amphiphilic polymers (TPS) and pH-activatable photosensitizers (LET-Br), and is further loaded with the anticancer drug docetaxel. Additionally, it is conjugated with small-molecule agonists of Toll-like receptor 7/8 (TLR 7/8) and cyclic RGD (cRGD) targeting peptides. Upon reaching the tumor site, the PNI undergoes hydrolysis, enabling the efficient release of anticancer drugs in response to the tumor microenvironment. Furthermore, under near-infrared (NIR) photoirradiation, the PNI exerts potent photodynamic effects to directly eliminate tumors. Remarkably, the PNI also functions as an in situ light-activated cancer vaccine, capable of inducing systemic antitumor immune responses and remodeling the immunosuppressive tumor microenvironment to establish long-lasting immune memory. This synergistic combination of photodynamic therapy and targeted antitumor immune responses effectively inhibits tumor growth. Thus, this study not only presents a novel strategy for designing vaccine-like prodrugs to precisely modulate cancer immunotherapy, but also opens new avenues for the development of advanced therapies for HCC.