Project Funding Details

Cancer immunotherapy, particularly immune checkpoint blockade (ICB) therapy, has emerged as a transformative approach in the treatment of various cancers, leveraging the body's immune system to identify and eliminate cancer cells. This therapeutic strategy has demonstrated remarkable efficacy in several cancer types, notably melanoma and non-small cell lung cancer, by targeting immune checkpoints such as PD-1/PD-L1 and CTLA-4. These checkpoints are critical modulators of immune activation, often exploited by cancer cells to evade immune surveillance. Osteosarcoma, the most common primary bone cancer, is characterized by aggressive and highly metastatic tumors originating in bone-forming tissues. The unique tumor microenvironment and the inherent biological characteristics of bone malignancies pose considerable challenges to the application of ICB therapy in bone cancers. Moreover, the management of extensive bone tumors necessitates surgical excision, which results in significant defects, frequently involving the removal of a limb. Consequently, the excision of the tumor necessitates the subsequent restoration of the surgically induced bone deficiency. The dense extracellular matrix and immunosuppressive TME in osteosarcoma significantly limit the effectiveness of ICB therapy by restricting immune cell infiltration and activity. The low mutational burden of osteosarcoma, leading to fewer neoantigens, further diminishes immune engagement. We propose a novel strategy combining 3D-printed graphene-based scaffolds with ICB therapy, augmented by PDT-induced pyroptosis, to overcome these barriers. This approach aims to shift the immunosuppressive, or "cold," TME towards a more immunogenic, or "hot," state, enhancing the potential for immune-mediated tumor destruction. Our research project aims to enhance the immunogenicity of osteosarcoma by integrating scaffold-based PDT to induce pyroptosis within the tumor microenvironment, thereby improving the efficacy of ICB therapy. The scaffolds, composed of PLGA and graphene oxide, are designed to fulfill dual roles: facilitating bone regeneration and converting near-infrared (NIR) light into localized heat for targeted PDT. The project will explore the design, optimization, and in vivo efficacy of these innovative scaffolds in osteosarcoma models. We will focus on graphene scaffold regenerative capabilities, the induction of pyroptosis through scaffold-mediated PDT, and the resultant immune responses. The synergistic effects of combining scaffold-mediated PDT with ICB therapy will be rigorously evaluated to achieve a robust and durable anti-tumor immune response. We anticipate that the localized photothermal effect of scaffold-mediated PDT will not only directly kill tumor cells but also induce pyroptosis, thereby releasing tumor antigens and damage-associated molecular patterns (DAMPs). This will recruit and activate antigen-presenting cells. The presentation of tumor antigens to T cells leads to T-cell activation, effectively bridging innate and adaptive immunity and "priming" patients for better immunological response to ICB therapy. By integrating cutting-edge materials science with advanced immunotherapeutic strategies, this project represents a multidisciplinary effort to overcome the current barriers in osteosarcoma treatment. The proposed approach not only offers a novel strategy for post-operative tumor control but also holds the potential to significantly improve the clinical outcomes for osteosarcoma patients, paving the way for new paradigms in cancer treatment.