Integrative analysis of TCGA transcriptomic states and DepMap dependencies prioritizes candidate vulnerabilities in immune-cold microsatellite-stable colorectal cancer

Microsatellite-stable/microsatellite instability-low colorectal cancer (MSS/MSI-L CRC) is generally resistant to immune checkpoint blockade, but the biological states underlying this resistance are heterogeneous. We integrated TCGA COAD/READ patient transcriptomic profiles, MSIsensor-based MSS/MSI-L classification, curated immune and stromal module scoring, focused differential expression and DepMap CRISPR dependency data to prioritize candidate vulnerabilities in immune-cold MSS CRC. Among 494 MSS/MSI-L tumours, 218 were classified as MSS intermediate, 102 as MSS immune-cold, 91 as MSS hot/inflamed and 83 as MSS barrier-high. MSS immune-cold tumours showed lower cytotoxic, IFN{gamma}-chemokine and antigen-presentation programmes than MSS hot/inflamed tumours, including reduced NKG7, CD8A, CXCL9, CXCL10 and LAG3 expression. MSS barrier-high tumours showed enrichment of stromal and extracellular-matrix programmes, including COL1A1, COL1A2 and COL3A1. Integration with DepMap CRISPR gene-effect data from 1208 cancer models, including 63 colorectal cancer models, separated tumour-cell-intrinsic dependencies from patient-derived microenvironmental signatures. Candidate target classes included ERBB2, VEGFA, PIK3CB, ATR/WEE1/CHEK1, HDAC1/HDAC3/BRD4 and BCL2L1/MCL1, while collagen genes were interpreted as stromal-barrier markers rather than tumour-cell dependencies. ERBB2 expression was higher in MSS immune-cold than MSS hot/inflamed tumours and further elevated in MSS barrier-high tumours, supporting ERBB2 as a candidate subset-associated signal that requires orthogonal HER2 validation. These findings support a stratified therapeutic framework for immune-cold, barrier-high and intermediate MSS CRC.