Pan-Cancer Immunogenomic Quantification of T and NK Cell Barriers in Solid Tumors Reveals Stromal–Metabolic Bottlenecks for Adoptive Cell Therapy

Adoptive cell therapy (ACT) has transformed the treatment of hematological malignancies but largely fails against solid tumors; the biological basis of this divide has rarely been quantified across cancer types. We analyzed uniformly reprocessed RNA-seq data (Toil pipeline) from TCGA (9,359 tumors, 33 cancer types), TARGET (734 pediatric tumors), and GTEx (7,862 normal samples). A 132-gene panel yielded T/natural killer (NK) infiltration, functional, metabolic, and stromal scores, integrated into a composite Solid Tumor Immune Accessibility Score (STIAS); six public single-cell datasets provided cellular validation. Median T- and NK-cell infiltration was about 30% lower in solid than in hematological tumors—a gap reflecting tissue of origin rather than recruitment failure. Single-cell analysis revealed per-cell enrichment of exhausted T-cell programs in solid tumors (23.6% versus 8.9%) and NKG2A upregulation on colorectal-tumor NK cells, while the dominant cohort-level barriers were stromal (extracellular matrix 3.79-fold) and metabolic (IDO pathway 1.27-fold). STIAS classified 14.5% of solid tumors as hematological-like “Accessible” phenotypes—reproduced in the pediatric TARGET cohort and enriched for the C2 (IFN-γ–dominant) immune subtype (26.4% versus 3.5%)—with each 0.1-unit increase associating with 46% and 40% higher hazard of death and progression. A bidirectional target atlas validated epithelial antigens (MUC1, ERBB2, CLDN18, CEACAM5, FAP, CD73) at the protein level and mapped hematological off-tumor risks; hematological-lineage signals (CD38, BCMA) proved predominantly immune-infiltrate-derived. Stromal–metabolic barriers dominate the solid tumor–specific axes of ACT resistance; STIAS-guided stratification and microenvironment reprogramming may extend cellular immunotherapy to solid malignancies.