JAK-STAT signaling pathway in cancer: from molecular mechanisms to clinical intervention

The Janus kinase/signal transducer and activator of transcription (JAK/STAT) signaling pathway is a conserved signaling network that mediates communication between extracellular cytokine stimulation and nuclear transcriptional responses. Beyond its established role in regulating cell proliferation, differentiation, immune responses, and tissue homeostasis, dysregulated JAK/STAT signaling contributes to tumor progression, immune evasion, therapeutic resistance, and remodeling of the tumor microenvironment (TME). Although canonical ligand-dependent JAK/STAT activation has been extensively characterized, increasing evidence indicates that STAT proteins also participate in diverse non-canonical signaling processes, including organelle-associated localization, liquid-liquid phase separation, epigenetic regulation, and JAK-independent activation. These mechanisms expand the functional complexity and context dependence of JAK/STAT signaling in cancer biology. Within the TME, persistent pathway activation modulates dynamic interactions among tumor cells, immune cells, and stromal components, thereby promoting immunosuppressive signaling networks and therapeutic resistance. In this review, we summarize current understanding of canonical and non-canonical JAK/STAT signaling mechanisms, regulatory networks governing pathway activation, and the multifaceted roles of JAK/STAT signaling in tumor progression and therapeutic resistance. We further discuss emerging therapeutic strategies targeting the JAK/STAT pathway, including selective kinase inhibitors, STAT-directed therapies, epigenetic modulators, and combination immunotherapeutic approaches, together with the major translational challenges that continue to limit clinical efficacy.