Targeting JAK–STAT signaling to enhance immune checkpoint inhibitor therapy in glioma: mechanisms and therapeutic opportunities

Immune checkpoint inhibitors (ICIs) have demonstrated limited clinical efficacy in glioma, largely owing to its highly immunosuppressive tumor microenvironment and complex mechanisms of immune evasion. The Janus kinase–signal transducer and activator of transcription (JAK–STAT) signaling pathway plays a pivotal role in regulating these processes and represents a potential therapeutic target for overcoming resistance to ICIs. In glioma, JAK–STAT signaling exerts context-dependent immunological functions. STAT1-mediated signaling supports antigen processing and presentation, whereas aberrant STAT3 activation promotes PD-L1 expression, immunosuppressive myeloid cell polarization, and T-cell dysfunction. These effects collectively influence tumor immunogenicity and antitumor immune responses. Targeting JAK–STAT signaling, particularly STAT3, may therefore provide opportunities to remodel the glioma immune microenvironment and improve responsiveness to immune checkpoint blockade. Although preclinical studies have demonstrated encouraging immunomodulatory effects, clinical investigations of JAK/STAT-targeted agents remain limited, and their ability to enhance ICI efficacy in patients with glioma has not been established. This narrative review examines the molecular mechanisms linking JAK–STAT signaling to immune checkpoint resistance in glioma, evaluates emerging therapeutic strategies, and highlights the challenges of translating pathway modulation into effective combination immunotherapy.