Tumor budding in colorectal cancer: partial EMT, microenvironmental remodeling, and metastatic competence.

Abstract

Tumor budding (TB) is a pathological hallmark of malignant invasion at the invasive front of colorectal cancer (CRC) and provides a morphologic window into early dissemination. In the International Tumor Budding Consensus Conference (ITBCC) framework, buds are single tumor cells or clusters of up to four cells, graded by hotspot counting to support standardized evaluation. Evidence from histopathology, single-cell profiling, spatially resolved analyses, and functional models links TB to invasion-competent tumor states. TB often tracks partial epithelial-mesenchymal transition, with weakened cell-cell adhesion, E-cadherin loss, altered β-catenin localization, and activation of integrin signaling, cytoskeletal remodeling, and extracellular matrix (ECM) degradation while retaining epithelial features. Spatial/trajectory analyses suggest that budding-rich regions concentrate plastic, stem-like programs biased toward migration and stress tolerance and lie close to intravasation. The TB niche also shows immune and metabolic specialization, with constrained dendritic-cell maturation and antigen presentation, reduced or dysfunctional CD8+ T-cell and NK-cell activity, and enrichment of tumor-associated macrophages and other suppressive myeloid programs. Hypoxia-driven glycolysis, lactate-associated acidification, adenosine signaling, and myeloid lipid-metabolic reprogramming can further stabilize invasive phenotypes and raise the threshold for immune control. Digital pathology and AI-enabled whole-slide analysis can improve scoring consistency and add spatial readouts linking TB patterns to immune contexture and stromal organization. Collectively, TB marks an interface between invasive tumor biology and the local microenvironment with direct relevance for risk stratification and therapeutic tailoring in CRC.