Periodic Reporting for period 1 - TRAIN (Tumor Regulation Assisted by Immunity and Nanotechnology)
Période du rapport: 2023-06-01 au 2025-06-30
Cancer is the leading cause of death among Europeans under the age of 65, with one in two people expected to face a cancer diagnosis during their lifetime. Despite important advances in prevention, diagnosis, and treatment, cancer continues to claim millions of lives, place heavy burdens on families, and generate significant pressure on healthcare systems and national economies. These realities highlight an urgent need for new therapeutic approaches, particularly for aggressive cancers such as pancreatic ductal adenocarcinoma (PAAD), which has a dismal prognosis and remains one of the most lethal malignancies in Europe. In response to this urgent medical and societal need, the European Union has launched “Europe’s Beating Cancer Plan”, which aims to reduce the burden of cancer by supporting innovative treatments, improving patient outcomes, and addressing inequalities in cancer care. Within this strategic framework, cancer immunotherapy represents one of the most promising advances, offering a durable and personalized treatment option. However, immunomodulation for cancer therapy is still in its infancy, and critical knowledge gaps remain, particularly regarding how tumour metabolism and immune cell activity can be regulated to improve therapeutic efficacy. The TRAIN project was conceived to address this gap by investigating a new class of molecularly engineered peptide nanomaterials capable of modulating amino acid metabolism within the tumour microenvironment (TME). The overarching goal was to create enzyme-responsive nanomaterials that release immunomodulatory amino acids, thereby enhancing the effectiveness of cancer immunotherapies. The TRAIN project provides a clear pathway from fundamental science to translational potential. By demonstrating proof-of-concept for enzyme-responsive peptide nanomaterials, the project contributes to new therapeutic strategies for PAAD, a cancer of high unmet clinical need.
During the course of the TRAIN project, significant progress was made towards developing and validating peptide-based nanomaterials as tools for metabolic modulation of the TME to boost cancer immunotherapy. A library of peptide amphiphiles (PAs), with the ability to self-assemble into nanofibers, was designed and synthesized. The nanomaterials were characterized using advanced biophysical methods (circular dichroism and electron microscopy), confirming their ability to self-assemble into stable nanostructures and to maintain structural integrity prior to enzymatic activation. To further make the designed nanosystem provide a combinatorial effect to the tumor cells, a potent antitumor drug (paclitaxel) was encapsulated within these nanofibers. The designed PAs demonstrated in vitro efficacy of the nanostructures against cancer cells. These findings provide proof-of-concept for the feasibility of in situ metabolic modulation of tumours using peptide nanomaterials. The main achievements were that enzyme-responsive peptide nanomaterials can be engineered to release selected amino acids, enabling targeted immunomodulation. In conclusion, TRAIN successfully achieved its primary objectives, advancing the field of peptide-based immunoengineering and opening new pathways for cancer treatment strategies in line with the EU’s Beating Cancer Plan.
Cancer immunotherapy is transforming treatment paradigms, yet its effectiveness remains limited in highly aggressive and immunosuppressive malignancies such as PAAD. A major barrier lies in the TME, where metabolic dysregulation, particularly amino acid depletion, suppresses the activation of immune effector cells. Conventional strategies, such as systemic administration of amino acid supplements, suffer from poor tumour specificity, limited bioavailability, and risk of systemic toxicity. Thus, there is a critical need for innovative approaches that can selectively modulate tumour metabolism and restore anti-tumour immunity. In this project, enzyme-responsive peptide nanomaterials were engineered to address this unmet need by releasing immunomodulatory metabolites directly within the TME. This represents a novel strategy compared to existing biologics or small-molecule modulators, as the peptides were designed to respond to tumour-associated proteases such as cathepsin B, which are abundantly expressed in PAAD. Proof-of-concept systems demonstrated controlled release of L-arginine (Arg), a metabolite known to enhance the activity of certain immune cells. These peptide nanomaterials go beyond the state-of-the-art by combining metabolic modulation with nanoscale precision, enabling a spatiotemporally controlled release of immunomodulators directly at the tumour site. Unlike systemic delivery methods, this approach minimizes off-target effects while ensuring locally effective concentrations of essential amino acid metabolites and enzyme inhibitors. Importantly, the modular design of the PA nanofibers allows multiple functionalities to be incorporated, opening possibilities for synergistic combination therapies within a single platform. The ultimate goal of this innovation is to provide a next-generation immunotherapy strategy where peptide-based nanomaterials act not only as drug carriers but as active participants in reshaping tumour metabolism and immune function. By achieving targeted, controlled release of amino acids, the project demonstrates a new pathway to improve outcomes for cancers of unmet clinical need, such as PAAD. These findings lay the groundwork for translational applications across other tumour types, extending the therapeutic relevance and reinforcing the broader impact of peptide nanomaterials in oncology.