The multifaceted role of SOCS3 in colorectal cancer: molecular mechanisms and clinical implications.

Colorectal cancer (CRC) remains a major cause of cancer-related mortality, particularly in advanced or metastatic disease. The Janus kinase/signal transducer and activator of transcription (JAK/STAT) pathway mediates cytokine-driven signaling, and its persistent activation contributes to tumor growth, invasion, immune escape, and therapeutic resistance. Suppressor of cytokine signaling 3 (SOCS3) is a key negative regulator of cytokine and growth factor signaling, especially the IL-6/JAK/STAT3 axis. This review summarizes the structure and physiological functions of SOCS3 and discusses its dysregulation in CRC initiation, progression, metastasis, prognosis, and treatment response. Current evidence indicates that SOCS3 is frequently downregulated in CRC through promoter methylation and post-transcriptional regulation by oncogenic microRNAs, leading to sustained STAT3 activation, increased proliferation, reduced apoptosis, and enhanced invasiveness. SOCS3 also interacts with MEK/ERK and PI3K/AKT signaling and influences the tumor microenvironment by regulating T-cell balance, PD-L1 expression, and macrophage activity. Clinically, reduced SOCS3 expression has been associated with lymph node metastasis, advanced TNM stage, and poorer prognosis, whereas higher SOCS3 levels may correlate with improved outcomes and chemosensitivity. Emerging therapeutic strategies include epigenetic modulation, JAK/STAT pathway inhibition, regulation of IL-6 signaling in adoptive T-cell therapy, AhR/IL-22 modulation, and FXR activation. Further translational studies are needed to validate SOCS3 as a biomarker and therapeutic target in CRC.