Uncertainty-aware and causal test-time adaptive foundation model for robust colorectal cancer pathology diagnosis.

Colorectal cancer (CRC) is a leading malignancy worldwide, where histopathological assessment of hematoxylin and eosin (H&E) stained whole-slide images remains the diagnostic gold standard. However, current computational pathology models suffer from domain shifts, unreliable uncertainty estimation, and spurious correlations, limiting clinical reliability. We present UAD-FM, an Uncertainty-Aware and Causally Adaptive Foundation Model that integrates epistemic-aleatoric uncertainty decomposition, causal test-time adaptation using do-interventions, and post-hoc calibration for trustworthy inference. Across five public CRC datasets (TCGA-COAD/READ, CRAG, DigestPath 2019, NCT-CRC-HE-100K, and LC25000), UAD-FM achieves superior accuracy, calibration, and domain robustness compared with existing foundation models and adaptation baselines. The model also produces interpretable uncertainty maps to support human-AI collaboration. UAD-FM provides a unified, transparent framework for reliable and generalizable CRC pathology diagnosis across heterogeneous clinical settings.