Spectroscopic Decryption of Epigenetic Remodeling Driving T Cell Exhaustion in Glioblastoma: A Path to Immunotherapeutic Reinvigoration

Glioblastoma (GBM) is the most aggressive and lethal primary brain tumour and remains largely refractory to immunotherapy owing to its profoundly immunosuppressive and metabolically reprogrammed tumour microenvironment (TME). A principal barrier is T-cell exhaustion—a terminally differentiated, dysfunctional state characterised by sustained expression of inhibitory immune checkpoints, transcriptional repression, epigenetic fixation, and progressive loss of cytotoxic effector function. This state is stabilised by chromatin remodelling, aberrant DNA methylation, nucleosome repositioning, histone post-translational modifications, and enhancer-landscape alterations, rendering exhausted T cells resistant to canonical immune-checkpoint blockade. High-resolution, multimodal spectroscopic technologies—including Raman scattering, Fourier-transform infrared (FTIR) spectroscopy, mass-spectrometry imaging (MSI), and surface-enhanced Raman spectroscopy (SERS)—have emerged as label-free, non-destructive, chemically sensitive tools capable of decoding the molecular and epigenomic architecture of exhausted T cells. These modalities afford spatiotemporal resolution of biomolecular alterations, capturing epigenetic asymmetries, metabolic flux, redox imbalance, lipidomic shifts, and nucleic-acid signatures that govern immune-cell fate within the GBM milieu. We hypothesise that synergistic integration of these advanced spectroscopic approaches with single-cell epigenomic and transcriptomic profiling will uncover exhaustion-specific molecular fingerprints, enable precise immune-subset stratification, and inform the development of targeted immunotherapies. This convergence of systems-level analytics with molecular interrogation could establish a transformative, non-invasive framework for immune monitoring and chromatin-directed reprogramming aimed at restoring T-cell stemness and reinvigorating durable anti-tumour immunity. By delineating spectroscopic correlates of epigenetic remodelling and immunometabolic dysfunction, this strategy may transcend current therapeutic limitations and facilitate biomarker-driven, mechanism-informed immunotherapy for GBM.