INSIGHT: Spatially resolved survival modelling from routine histology crosslinked with molecular profiling reveals prognostic epithelial-immune axes in stage II/III colorectal cancer

TL;DR

INSIGHT is a graph neural network that predicts survival in stage II/III colorectal cancer from routine histology, revealing spatial tissue organization and molecular features linked to prognosis, outperforming traditional staging methods.

Contribution

The paper introduces INSIGHT, a novel spatially resolved survival prediction model using histology images combined with molecular data, providing detailed prognostic insights beyond existing methods.

Findings

INSIGHT outperforms pTNM staging in prognostic accuracy.

Spatial risk maps identify key histopathological features.

Integrated molecular analysis reveals prognostic epithelial-immune interactions.

Abstract

Routine histology contains rich prognostic information in stage II/III colorectal cancer, much of which is embedded in complex spatial tissue organisation. We present INSIGHT, a graph neural network that predicts survival directly from routine histology images. Trained and cross-validated on TCGA (n=342) and SURGEN (n=336), INSIGHT produces patient-level spatially resolved risk scores. Large independent validation showed superior prognostic performance compared with pTNM staging (C-index 0.68-0.69 vs 0.44-0.58). INSIGHT spatial risk maps recapitulated canonical prognostic histopathology and identified nuclear solidity and circularity as quantitative risk correlates. Integrating spatial risk with data-driven spatial transcriptomic signatures, spatial proteomics, bulk RNA-seq, and single-cell references revealed an epithelium-immune risk manifold capturing epithelial dedifferentiation and fetal programs, myeloid-driven stromal states including $\mathrm{SPP1}^{+}$ macrophages and $\mathrm{LAMP3}^{+}$ dendritic cells, and adaptive immune dysfunction. This analysis exposed patient-specific epithelial heterogeneity, stratification within MSI-High tumours, and high-risk routes of CDX2/HNF4A loss and CEACAM5/6-associated proliferative programs, highlighting coordinated therapeutic vulnerabilities.