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.
