Metastatic cancer remains the leading cause of cancer-related mortality, with the lung being a frequent site of tumour dissemination. A key barrier to therapeutic success is the establishment of a profoundly immunosuppressive tumour microenvironment (TME), orchestrated by tumour-derived signals that trigger immune evasion mechanisms. Invariant Natural Killer T (iNKT) cells are uniquely positioned to overcome this barrier due to their ability to rapidly activate and coordinate both innate and adaptive immune responses. However, systemic activation of iNKT cells using α-galactosylceramide (αGalCer) leads to functional exhaustion, limiting its clinical applicability.

This project explores a novel strategy to harness iNKT cell-mediated antitumour immunity by delivering αGalCer intranasally in a nanoparticle formulation (nano-αGalCer), designed to induce repeated, localized activation of pulmonary iNKT cells without inducing hypo-responsiveness. We hypothesize that sustained iNKT cell activation will remodel the TME by reducing immunosuppressive cell populations, enhancing TRAIL-mediated cytotoxicity, and sensitizing metastatic tumour cells to apoptosis.

Using a well-established mouse model of melanoma lung metastasis, we will (i) assess the immunological impact of repeated nano-αGalCer administration in the lung, (ii) evaluate its therapeutic efficacy, (iii) decode the underlying molecular mechanisms via transcriptomic profiling, and (iv) validate the translational relevance of our findings through comparative analysis with human lung metastasis datasets. By linking nanotechnology, immunotherapy, and bioinformatics, this project aims to establish nano-αGalCer as a powerful and clinically viable immunotherapeutic approach to counteract metastatic immune evasion and restore effective tumour control in the lung.