Emerging Roles of ETV4 in Tumor Microenvironment Remodeling: Mechanisms and Therapeutic Targeting

ETS variant transcription factor 4 (ETV4), a member of the PEA3 subfamily of ETS transcription factors, has emerged as an oncogenic transcriptional regulator that promotes tumor growth, invasion, metastasis, and therapeutic resistance. Although previous studies have largely focused on its cancer cell-intrinsic functions, accumulating evidence suggests that ETV4 also contributes to remodeling of the tumor microenvironment (TME). ETV4 influences diverse microenvironmental processes, including metabolic adaptation, immune crosstalk, stromal and extracellular matrix remodeling, and cellular responses to hypoxic and mechanical stress. It has also been implicated in extracellular vesicle- and non-coding RNA-mediated communication, further supporting its role in coordinating reciprocal interactions between tumor cells and their surrounding microenvironment. Collectively, these findings position ETV4 as a molecular interface linking oncogenic signaling to TME reprogramming. In this review, we synthesize current evidence on the involvement of ETV4 in metabolic, immune, stromal, extracellular matrix, hypoxic, and intercellular communication networks. We further discuss emerging therapeutic strategies aimed at suppressing ETV4-associated activity through inhibition of upstream RTK-MAPK signaling, disruption of transcriptional cofactor dependencies, modulation of protein stability, and targeting of ETV4-dependent microenvironmental interactions. A more comprehensive understanding of ETV4-mediated tumor-microenvironment crosstalk may uncover context-specific vulnerabilities and provide a rationale for combination therapeutic strategies in ETV4-active malignancies.