Signaling pathways and targeted interventions for precancers.
Precancers, defined as normal-appearing or morphologically altered tissues with a risk of oncogenesis, exhibit various detectable manifestations across anatomical sites, including epithelial dysplasia, metaplasia, hyperplasia, and stromal fibrosis. Considering the prevailing assumption that most cancers arise from precancers, early intervention at the precancerous stage has immense potential to reduce cancer-related morbidity and mortality. However, the complex signaling networks governing precancer initiation and progression remain elusive, hampering the development of effective targeted interventions. This review synthesizes three critical dimensions of precancer biology: historical foundations tracing the conceptual evolution of precancer research over the past century; mechanisms underlying the multistep progression of precancer biology, encompassing epithelial and macro/microenvironmental remodeling; and signaling networks cataloging dysregulated pathways and their therapeutic potential. Over 10 signaling pathways, including the transforming growth factor-β (TGF-β), p53, Wnt, phosphatidylinositol 3-kinase (PI3K), and mitogen-activated protein kinase (MAPK) pathways, drive multistep malignant transformation. We further synthesize emerging evidence supporting microenvironmental dominance, proposing the novel "soil degeneration" hypothesis. This paradigm shift underscores the necessity for dual-window intervention in which early-phase microenvironmental normalization prevents the establishment of precancerous lesions and advanced-phase treatment concurrently addresses epithelial malignancy and stromal degeneration. This review bridges foundational molecular discoveries with translational clinical potential and advocates for precision intervention frameworks that extend from biomarker-guided risk assessment to synergistic remodeling of the precancer microenvironment, thereby redefining precancer intervention in the molecularly targeted era.