Tissue-Agnostic Cellular Morphometric Biomarkers for Risk-Adapted Management Across Gastrointestinal Precancerous Lesions and Cancers.

While precision oncology increasingly adopts tissue-agnostic paradigms, current strategies remain heavily reliant on molecular alterations, with limited relevance to early-stage cancers and precancerous lesion management. Here we present an unsupervised and interpretable artificial intelligence framework that defines tissue-agnostic cellular morphometric biomarkers (CMBs) capturing conserved tumor microenvironment (TME) architectures associated with cancer progression across gastrointestinal (GI) organs. Discovered from colorectal cancer whole-slide images and validated in gastric and esophageal malignancies within a multi-center cohort of 2,602 patients, a 13-CMB signature demonstrates robust cross-GI tissue transferability and prognostic impact. Importantly, beyond prognostic value in pan-GI cancers, the 13-CMB signature enables risk stratification of precancerous lesions and early-stage cancers, addressing a key unmet need in clinical decision-making where molecular profiling is often impractical or insufficient. The CMB-based risk scores support risk-adapted management, including individualized surveillance intervals and tailored intervention strategies. Integrative analyses using bulk and single-cell RNA sequencing and immunohistochemistry profiling show that CMBs correspond to biologically interpretable morphological states of the TME, including immune-excluded and stromal-dominant architectures. Together, this study establishes a biologically transparent, tissue-agnostic CMB framework that links conserved TME organization to clinically actionable risk assessment, providing a scalable approach for early cancer management and precision oncology.