NanoImmunoRT · Synergizing enhanced radiotherapy with tumor-associated macrophages-targeted immunotherapy in glioblastoma with multimodal therapeutic nanoparticles

Synergizing enhanced radiotherapy with tumor-associated macrophages-targeted immunotherapy in glioblastoma with multimodal therapeutic nanoparticles

Glioblastoma (GBM) is the most aggressive and common form of primary brain cancer in adults. Despite advances in surgery, radiotherapy (RT), and chemotherapy, the prognosis for GBM patients remains poor, with median survival rarely exceeding 15 months. Two major challenges limit the efficacy of current treatments. The immunosuppressive tumor microenvironment, particularly the presence of tumor-associated macrophages (TAMs), which promote tumor growth and suppress anti-tumor immune responses, and hypoxia (low oxygen levels) within the tumor which further exacerbates these issues, reducing the effectiveness of RT and immunotherapy. Addressing these limitations requires innovative, multimodal therapeutic strategies that can simultaneously enhance RT efficacy, reprogram the tumor immune microenvironment, and overcome hypoxia. Project objectives The NanoImmunoRT project aims to develop a synergistic therapeutic strategy combining radiosensitization and TAM-targeted immunotherapy using multimodal therapeutic nanoparticles (MTNPs). The project leverages zeolite-based nanoparticles (LTL types) functionalized with manganese (Mn) and gadolinium (Gd) to enhance catalytic activity for oxygen generation and radiosensitization, and toll-like receptor (TLR) agonists (e.g., R848) to reprogram TAMs and stimulate anti-tumor immune responses. The overall goal is to create a single nanoparticle platform that can: - Decompose tumoral hydrogen peroxide (H2O2) into oxygen (O2), alleviating hypoxia and improving RT efficacy. - Act as a radiosensitizer, enhancing DNA damage in cancer cells during RT. - Re-educate TAMs from a pro-tumor (M2) to an anti-tumor (M1) phenotype, boosting the immune response against the tumor. Project Pathway to Impact The project introduces a novel MTNP formulation (LTL-Mn/Gd nanozeolites) with superior catalytic activity and radiosensitizing properties, addressing key limitations of current GBM therapies. In vitro and in vivo studies demonstrated that LTL-Mn/Gd nanozeolites enhance RT efficacy, reduce tumor hypoxia, and synergize with immunotherapy (R848), leading to significant tumor growth inhibition and prolonged survival in murine models. The project provides a proof-of-concept for combining RT and immunotherapy using MTNPs, paving the way for future preclinical studies in GBM and other hypoxic, immune-suppressive tumors. Scale and significance of expected impacts The project’s findings could help reshape the field of radioimmunotherapy, demonstrating the feasibility of using MTNPs to overcome hypoxia and immune suppression in GBM. The development of patentable MTNPs could stimulate innovation in the biotech sector, creating new markets and job opportunities. Moreover, by engaging with patients, clinicians, and the public, the project ensures that its innovations are accessible, understandable, and aligned with societal needs. Conclusions The NanoImmunoRT project is a pioneering effort to combine nanotechnology, radiotherapy, and immunotherapy into a single, synergistic treatment for GBM. By addressing hypoxia, radioresistance, and immune suppression, the project offers a holistic solution to the complex challenges of GBM therapy. Its results are expected to advance scientific knowledge, drive economic growth, and, most importantly, improve the lives of patients facing this aggressive disease. The project’s alignment with European health priorities and its commitment to sustainability and public engagement further underscore its potential for lasting impact.

Data: CORDIS, © European Union