Luetge, M.; Nassiri, S.

Motivation: The tumor microenvironment (TME) dictates cancer progression and therapeutic response, yet translating TME subtypes into robust clinical biomarkers remains a significant challenge. Existing classification models typically rely on static gene signatures and cohort-dependent normalization, making them ill-suited for application to the small, unbalanced datasets common in early-phase clinical trials. To better guide drug development, methods are required that offer the flexibility to target specific biological contexts and bridge the gap between the discovery of tumor archetypes and their robust translation to individual patient samples. Results: We developed TumorArchetypeR, a modular R package that unifies unsupervised subtype discovery with the generation of rank-based, single-sample classifiers. By leveraging a systematic parameter grid search, the framework identifies stable, data-driven subtypes rather than relying on arbitrary defaults. Crucially, to ensure clinical translatability, the package includes a module to train a robust classifier using binary gene-pair rules, enabling prediction without cohort-level preprocessing. Applying TumorArchetypeR to colorectal cancer, we resolved the heterogeneity of fibrotic tumors, distinguishing an immunosuppressive "Immune-enriched/Fibrotic" state from an immune-excluded "Fibrotic/Myeloid" phenotype. Furthermore, we identified a distinct "Th/B-cell enriched" archetype associated with superior survival, a group largely obscured by existing pan-cancer models. With our rank-based classifier demonstrating robust performance on previously unseen samples, these findings highlight TumorArchetypeR as a scalable, end-to-end solution for refining patient stratification and optimizing precision oncology strategies. The TumorArchetypeR package and documentation are openly available on GitHub at https://github.com/lutgem/TumorArchetypeR.