Glioblastoma (GB) remains highly resistant to immunotherapy, including NK cell-based approaches, largely because of its profoundly immunosuppressive tumor microenvironment (TME). Elevated TGF-β levels, extensive cellular heterogeneity, and complex interactions between cancer cells, immune infiltrates, stromal elements, and the extracellular matrix all contribute to limited therapeutic efficacy and hinder NK cell activation and function.

Fig.1 Key challenges in glioblastoma.

A major challenge in GB research is that most current studies rely on bulk or single-cell profiling, which obscures the spatial organization of the TME and the local interactions that shape treatment response. To address this limitation, we recently established a patient-derived GB organoid model that preserves intra- and intertumor heterogeneity, histological features, and stromal diversity, making it an ideal platform for spatially resolved analysis of therapy response.

This project will focus on how NK cell therapy, particularly in combination with TGF-β inhibition, reshapes the GB TME and the specialized niches that support glioblastoma stem cells (GSCs). GSCs are key drivers of tumor progression, recurrence, and therapy resistance, and their interaction with the surrounding niche may protect them from immune attack even when TGF-β signaling is blocked. By studying these responses in spatial context, the project aims to identify molecular signatures of GSC susceptibility and resistance, reveal niche-specific escape mechanisms, and uncover strategies to overcome immunotherapy resistance in GB.

We are open for collaborations, if you’re interested please contact Bernarda Majc PhD.