Using spatial transcriptomics (GeoMx), the study reveals that primary resistance to ICIs in mTLS‐positive tumours is driven by two distinct CAFs subsets: FAP+αSMA+ CAFs, linked to CD8+ T cell exhaustion and inflammatory pathways, and MYH11+αSMA+ CAFs, which promote immunosuppression via CD4+ Treg infiltration. Here, CD8A is linked to neoplasm.