Tumor-infiltrating lymphocyte (TIL) therapy, recently approved by the FDA for melanoma, is an emerging modality for cell-based immunotherapy. However, its application in immunologically "cold" tumors such as glioblastoma remains limited due to sparse T cell infiltration, antigenic heterogeneity, and a suppressive tumor microenvironment. To identify genomic and spatial determinants of TIL expandability, we performed integrated, multimodal profiling of high-grade gliomas using spectral flow cytometry, TCR sequencing, single-cell RNA-seq, Xenium transcriptomics, and CODEX spatial proteomics. Comparative analysis of TIL-generating (TIL⁺) versus non-generating (TIL⁻) tumors revealed that expression, structured perivascular immune clustering, and tumor-intrinsic metabolic programs such as were associated with successful TIL expansion. In contrast, TIL⁻tumors were enriched for neuronal lineage signatures, immunosuppressive transcripts including and , and tumor-connected macrophages. This study defines spatial and molecular correlates of TIL manufacturing success and establishes a genomics-enabled selection platform for adoptive T cell therapy. The profiling approach is now being prospectively implemented in the GIANT clinical trial (NCT06816927), supporting its translational relevance and scalability across glioblastoma and other immune-excluded cancers.