Metabolically optimised NK cell therapies for Glioblastoma

Glioblastoma Multiforme is one of the most aggressive forms of brain cancer, and despite advances in surgery, radiation, and chemotherapy, survival rates remain dismal. A promising frontier lies in harnessing the body’s own immune system, specifically, Natural Killer (NK) cells, which are hard-wired to detect and destroy abnormal cells. Yet inside glioblastoma tumors, NK cells face a hostile environment. Tumor-derived metabolites, including fatty acids and other by-products, overload the cells’ metabolism and blunt their ability to kill. Our project aims to understand and overcome this blockade. Using advanced imaging and metabolic assays, we are mapping how glioblastoma creates an immunosuppressive niche and how NK cells respond under stress. A particular focus is on identifying the molecular “sensors” that detect when NK cells are overwhelmed by toxic levels of fatty acids, such as palmitate, which is abundant in the tumor microenvironment. By pinpointing these stress-sensing pathways, we aim to rewire NK cells so they can withstand metabolic overload and remain functional inside the tumor. This involves genetic engineering strategies to boost resilience, as well as testing combinations of fatty acids and nutrients to reveal protective mechanisms. In parallel, we are exploring how patient-derived tumor cells shape this environment and using them as models for NK cell therapy design. If successful, these efforts could lead to a new generation of engineered NK cells that are not only effective killers but also metabolically “stress-tolerant”, a crucial step toward durable immunotherapies against glioblastoma.

Background: Glioblastoma Multiforme (GBM) is an incurable form of brain cancer. However, there is now an opportunity to apply the advances in cellular immunotherapy to treat GBM. Natural Killer (NK) cells are cytotoxic lymphocytes that kill tumour cells. However, GBM tumours create an environment rich in metabolites (eg. fatty acids) and proteins (eg. TGF?) that potently suppress NK cell metabolism and cytotoxicity. Hypothesis: The metabolic microenvironment of GBM is a key driver of NK cell dysfunction and a limiting factor for NK cell immunotherapies. Aims: Our primary aim is to establish the nature the suppressive metabolic tumour microenvironment (TME) and to understand how this interferes with infiltrating NK cells. This will guide our secondary aim of developing novel approaches to bolster NK cell metabolism for enhanced cytotoxic activities against GBM tumours. Methods: Spatial distribution of the metabo-lipidome and TGF? actions within GBM tumours will be performed by DESI-/MALDI-mass spec imaging (Germany) and multiplex immunofluorescence imaging (Belgium). Modelling will estimate the relationship between metabolites, lipids, TGF? pathway components and the immunological landscape with respect to NK cells abundance and functionality (Ireland/Germany). Flow cytometry, confocal and electron microscopy (Ireland/Norway), will define the metabolic phenotype of GBM infiltrating NK cells. Identified strategies such as genetic engineering of NK cells and/or antibody blockade of TGF? axis for metabolic resilience will be tested in a murine GBM model and applied to human NK cell therapeutic platforms (Norway) towards generating cellular products for clinical trials.