JAK inhibition in PD-1 immunotherapy and tumor microenvironment

Targeting the programmed cell death 1 (PD-1)/PD-L1 axis has revolutionized cancer therapy; however, the durability of clinical responses is frequently compromised by chronic inflammation and an immunosuppressive tumor microenvironment (TME). The Janus kinase/signal transducer and activator of transcription (JAK/STAT) signaling pathway serves as a central intracellular node integrating cytokine signals that drive these resistance mechanisms. While physiological JAK/STAT signaling is essential for antitumor immunity, its persistent aberrant activation promotes malignant progression, upregulates PD-L1 expression, and orchestrates an immunosuppressive landscape by recruiting myeloid-derived suppressor cells (MDSCs) and polarizing tumor-associated macrophages (TAMs) toward an M2 phenotype, ultimately leading to T cell exhaustion. This review comprehensively elucidates the multifaceted role of JAK/STAT signaling in shaping the immune architecture of both hematologic and solid tumors. We examine the molecular crosstalk between JAK/STAT activation and key immune subsets within the TME and discuss the rationale for repurposing JAK inhibitors-established agents for autoimmune disorders-as adjuvants to immunotherapy. Emerging preclinical and clinical evidence suggests that combining selective JAK inhibition with PD-1 blockade can disrupt inflammatory feedback loops, reprogram the TME, and overcome resistance to immune checkpoint inhibitors. This synergistic strategy represents a promising therapeutic frontier for improving outcomes in refractory malignancies.