Development and validation of a stromal myeloid-fibrotic index and a tumor-intrinsic immune evasion index for molecular stratification in colorectal cancer.

Immune checkpoint blockade has limited efficacy in microsatellite-stable colorectal cancer, where immune resistance may reflect stromal remodeling, tumor-intrinsic immune evasion, or both. Bulk classifications such as the Consensus Molecular Subtypes can mix these mechanisms into discrete labels. We developed two continuous indices computable from bulk data, a stromal myeloid fibrotic index (SMI) based on TGFβ signaling and an SPP1+ macrophage program, and a residualized immune evasion index (IEI_resid) combining CIN70 with reduced antigen presentation after adjustment for tumor purity and immune content. Across three cohorts (n = 1,243), SMI was associated with macrophage abundance, while IEI_resid was associated with lower antigen presentation scores. In CPTAC COAD, SMI aligned with extracellular matrix and stromal protein markers, whereas IEI_resid aligned with reduced antigen presentation proteins and a composite APM protein score. SMI and IEI_resid improved model fit beyond CMS and beyond ESTIMATE stromal and immune scores. Spatial transcriptomics in two independent tumors provided supportive evidence for compartment-level separation of stromal and epithelial programs and higher immune signal in stromal-dominant regions. These results provide a practical framework to model stromal remodeling and tumor-intrinsic antigen presentation features as partially separable dimensions in colorectal cancer.