Metastasis remains the primary cause of cancer-related mortality, driven not only by intrinsic genetic alterations but also by dynamic reprogramming of the post-metastatic microenvironment. Recent advances in multi-omics technologies—including single-cell transcriptomics, spatial profiling, methylome analysis, chromatin architecture mapping, and proteomics—have reshaped our understanding of metastatic ecosystems and revealed key regulatory nodes that coordinate tumor progression. Among these, SERPINE2 has emerged as a convergent mediator across diverse cancer types. Multi-layered evidence demonstrates that SERPINE2 integrates tumor-intrinsic signaling and microenvironmental remodeling. Mechanistically, SERPINE2 stabilizes oncogenic receptors such as EGFR by inhibiting ubiquitination-dependent degradation, sustains downstream STAT3/ERK activation, and enhances DNA damage response through ATM phosphorylation and homologous recombination repair. Concurrently, as a secreted factor, SERPINE2 promotes cancer-associated fibroblast activation, M2 macrophage polarization, extracellular matrix remodeling, and angiogenesis, collectively fostering immune suppression and metastatic persistence. These dual tumor-intrinsic and stromal functions position SERPINE2 as a molecular hub in post-metastatic adaptation. Targeting SERPINE2 may therefore represent a paradigm shift in advanced cancer therapy by simultaneously disrupting oncogenic persistence, genome maintenance, and immune exclusion. This review synthesizes multi-omics insights into SERPINE2-driven microenvironmental reprogramming and discusses emerging therapeutic strategies integrating molecular targeting and immunotherapy in metastatic cancers.
Yi et al. (Wed,) studied this question.