Mapping Tumor-Microenvironment dependencies with TMEformer: A spatial foundation framework enabling in silico perturbation

Abstract

Despite the fundamental role of spatial context in driving tumor progression, most current computational models for virtual perturbation have largely overlooked its importance. Here, we introduce TMEformer, a tumor microenvironment-aware deep learning framework that leverages high-resolution spatial transcriptomics to jointly model intrinsic tumor cell programs and local microenvironmental signals by explicitly incorporating spatial architecture. Validated across diverse tumor spatial transcriptomic cohorts, TMEformer enables virtual perturbations that capture functional dependencies within local cellular ecosystems. Despite being trained on cancer-specific spatial datasets, TMEformer outperforms baseline models pretrained on large-scale corpora in capturing key tumor transitions, including lineage plasticity and the emergence of therapy resistance. Systematic perturbation analyses prioritize tumor-intrinsic transcription factors and TME-derived ligands that drive disease progression, recovering established regulators and revealing novel candidates. Furthermore, TME- derived embeddings improve the spatial stratification of tumor cells and align more closely with pathological architecture. Together, TMEformer establishes a general framework for modeling tumors as spatially coupled, perturbable ecosystems. An online TMEformer web platform for perturbation prediction, analysis, and visualization is available at http://www.pradcellatlas.com.