Al-deka, A. | bioRxiv Science

bioRxiv2026

Targeting glucocorticoid signalling in dendritic cells for glioblastoma treatment

Glioblastoma (GBM) remains a devastating disease with few meaningful therapeutic advances over the past three decades. Dendritic cell (DC) vaccination is a promising immunotherapeutic strategy for GBM, but its efficacy is limited by the clinical use of dexamethasone to control cerebral oedema and associated symptoms. Here we show that steroid signalling is a central regulator of DC dysfunction in GBM. Through targeted metabolomics of primary GBM samples, we identified a steroid-rich tumour microenvironment in which dexamethasone is present at high levels. Across bulk and single-cell transcriptomic and epigenomic datasets, NR3C1 emerged as the dominant steroid receptor in GBM immune cells and was negatively associated with activated DC states. In patient-derived DCs, dexamethasone altered NR3C1 chromatin occupancy, induced broad transcriptional and chromatin remodelling, and suppressed co-stimulatory antigen-presentation and cytokine programmes. DC-specific deletion of Nr3c1 restricted syngeneic glioblastoma growth, enhanced DC activation, promoted cytotoxic CD8+ T cell responses and remodelled myeloid states in vivo. In GBM patient-derived DCs, pharmacological or non-viral CRISPR-mediated disruption of NR3C1 restored inflammatory, antigen presentation and T cell-stimulatory programmes, enhanced antigen-specific CD8+ T cell priming, and improved tumour lysate-loaded DC vaccination. Together, these findings identify glucocorticoid signalling as a key barrier to DC immunotherapy in GBM and establish NR3C1-targeted, steroid-resistant DCs as a potential therapeutic strategy.

immunology↗

bioRxiv2025

Single cell functional immunogenomics of the fallopian tube reveals a precursor immune surveillance network for ovarian cancer prevention

The fallopian tube (FT) is increasingly recognized as the site of origin for high-grade serous ovarian cancer (HGSOC), yet its immune landscape and potential role in tumor surveillance remain poorly understood. Here, we employ single-cell RNA sequencing (scRNA-seq) and paired single-cell T-cell receptor sequencing (scTCR-seq) to profile tissue-resident memory-like T cells (TRMLs) from matched non- cancerous FT, metastatic omental tumors, and peripheral blood in HGSOC patients. Surprisingly, we identify a substantial clonal and functional overlap between TRMLs from non-cancerous FT and tumor- infiltrating TRMLs, with 18.4% of tumor TRML clonotypes being shared with FT TRMLs, significantly exceeding overlap with circulating T cells. Shared TCR clonotypes are preferentially enriched in exhausted CD8+ T cells (CD8-Tex) and proliferative exhausted CD8+ subsets, suggesting prior antigenic exposure. Notably, we identify a previously uncharacterized CD8+ SIK3-high subset enriched in tumors, with gene expression signatures implicating epigenetic plasticity and metabolic adaptation. Functionally, non-cancerous FT-derived TRMLs recognize autologous tumor antigens, as evidenced by robust IFN-{gamma} responses in tumor organoid co-culture assays and CD137 upregulation. Whole-genome and transcriptomic analyses reveal shared somatic mutations between the FT and tumor, supporting the FT as the tumors evolutionary origin. Predicted tumor neoantigens elicit TRML responses in the non-cancerous FT, and single-cell TCR profiling confirms that neoantigen-reactive T cells in FT share clonotypes with tumor-infiltrating TRMLs, further reinforcing their role in early immune surveillance. Importantly, FT-derived TRMLs exhibit lower exhaustion signatures than their tumor counterparts, suggesting their potential as a preferable source for adoptive T cell therapies. Our findings uncover a precursor immune surveillance network in the FT and provide a rationale for leveraging FT-resident T cells in cancer immunotherapy and prevention.

immunology↗