Prostate cancerremains a global health challenge, ranking as the second most common malignancy among men. While early-stage disease can be effectively managed, advanced forms-particularly metastatic castration-resistant prostatecancer(mCRPC)-pose significant therapeutic hurdles. A growing body of evidence highlights the pivotal role of SOX transcription factors, with SOX2 emerging as a central driver in tumor growth, spread, and resistance to therapy. SOX2 is intricately linked to the fate of cancer stem/progenitor cells, influencing processes such as cell proliferation, apoptosis resistance, and epithelial-mesenchymal transition (EMT), which fuel invasion and metastasis. Elevated SOX2 levels are frequently observed in aggressive tumors and are associated with poor prognosis. Its activity extends to shaping tumor lineage plasticity, enabling cancer cells to adapt and survive under therapeutic pressure. This adaptability often facilitates transformation into neuroendocrine prostate cancer (NEPC), an aggressive variant with limited treatment options. At the molecular level, SOX2 operates within a complex regulatory network, interacting with key transcription factors, non-coding RNAs, and epigenetic modifications. It is also a critical node in multiple signaling pathways, including PI3K/AKT, Hedgehog, Wnt/β-catenin, and TGF-β, which collectively sustain cancer stem cell traits and drive disease progression. Importantly, SOX2’s regulation involves both upstream inducers such as BRN2, TRIB2, and NRP2, and downstream effectors including LSD1, H19, SPINK1, and ASCL1—each contributing to tumor aggressiveness and therapeutic resistance. SOX2’s role in treatment resistance is particularly significant. It supports resistance to chemotherapy by inducing a reversible quiescent state and activating survival pathways, while also mediating resistance to nuclear hormone receptor signaling inhibitors through modulation of cell cycle regulators and glucocorticoid receptor expression. This makes SOX2 a critical obstacle in sustaining long-term therapeutic success in advanced prostate cancer. The potential of targeting SOX2-directly or indirectly-offers a promising avenue for innovation. Strategies may include disrupting its protein-protein interactions, modulating upstream regulators or downstream pathways, and harnessing small-molecule inhibitors to selectively curb its tumor-promoting functions. However, given SOX2’s importance in normal tissue regeneration, therapeutic approaches must balance efficacy with safety to minimize adverse effects. As research advances, understanding the multifaceted role of SOX2 could pave the way for more precise, effective, and durable treatments, offering hope for patients battling the most aggressive forms of prostate cancer. Guotu Du, Xiang Huang, Peng Su, Ying Yang, Shicheng Chen, Tianyu Huang, Neng Zhang, The role of SOX transcription factors in prostate cancer: Focusing on SOX2, Genes & Diseases, https://doi.org/10.1016/j.gendis.2025.101692.