Prostate cancer remains a formidable global health challenge, standing as the second most prevalent malignancy among men. While localized forms of the disease are often amenable to successful intervention, advanced manifestations, particularly metastatic castration-resistant prostate cancer (mCRPC), present significant obstacles to effective treatment. Emerging research increasingly emphasizes the crucial involvement of SOX transcription factors, with SOX2 notably surfacing as a key orchestrator of tumor proliferation, dissemination, and resistance to therapeutic agents.

SOX2 is intimately connected with the trajectory of cancer stem/progenitor cells, exerting influence over fundamental biological processes such as cellular multiplication, evasion of programmed cell death, and epithelial-mesenchymal transition (EMT), all of which facilitate tumor invasion and spread. Elevated concentrations of SOX2 are frequently detected in aggressive cancerous growths and correlate with unfavorable patient outcomes. Its influence extends to shaping the capacity of tumor cells for lineage plasticity, enabling them to adapt and endure under the selective pressures of therapy. This inherent adaptability frequently contributes to the transformation into neuroendocrine prostate cancer (NEPC), a particularly aggressive variant with limited therapeutic avenues. On a molecular scale, SOX2 functions within an intricate regulatory network, engaging in interactions with pivotal transcription factors, non-coding RNAs, and epigenetic modifications. It also serves as a critical nexus within multiple signaling pathways, including PI3K/AKT, Hedgehog, Wnt/β-catenin, and TGF-β, which collectively sustain the characteristics of cancer stem cells and propel disease advancement. Significantly, the regulation of SOX2 encompasses both upstream activators, such as BRN2, TRIB2, and NRP2, and downstream mediators, including LSD1, H19, SPINK1, and ASCL1, each contributing to the heightened aggressiveness and therapeutic recalcitrance of the tumor.

The capacity of SOX2 to foster treatment resistance is particularly noteworthy. It confers resistance to chemotherapy by inducing a reversible dormant state and activating survival mechanisms, while also mediating resilience against nuclear hormone receptor signaling inhibitors through its influence on cell cycle regulators and the expression of glucocorticoid receptors. Consequently, SOX2 represents a significant impediment to achieving sustained long-term therapeutic success in managing advanced prostate cancer. The prospect of modulating SOX2—whether directly or indirectly—offers a promising direction for innovative interventions. Potential strategies encompass disrupting its protein-protein interactions, modulating its upstream regulators or downstream pathways, and employing small-molecule inhibitors to selectively curtail its tumor-promoting activities. However, given SOX2's indispensable role in normal tissue regeneration, therapeutic strategies must carefully balance the pursuit of effectiveness with the imperative of safety to mitigate undesirable side effects. As scientific inquiry progresses, a deeper comprehension of SOX2's multifaceted involvement could illuminate pathways toward more precise, potent, and lasting treatments, thereby offering renewed hope to individuals confronting the most aggressive manifestations of prostate cancer.