{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,5]],"date-time":"2026-11-05T00:54:07Z","timestamp":1793840047868,"version":"4.6.1"},"reference-count":112,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,4,2]],"date-time":"2026-04-02T00:00:00Z","timestamp":1775088000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:p>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\u2014established agents for autoimmune disorders\u2014as 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.<\/jats:p>","DOI":"10.3389\/fimmu.2026.1790936","type":"journal-article","created":{"date-parts":[[2026,4,2]],"date-time":"2026-04-02T05:26:08Z","timestamp":1775107568000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":30,"title":["JAK inhibition in PD-1 immunotherapy and tumor microenvironment"],"prefix":"10.3389","volume":"17","author":[{"given":"Ziyuan","family":"Liu","sequence":"first","affiliation":[{"name":"Department of Orthopedics, The Second Hospital of Jilin University","place":["Changchun, Jilin, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiaqi","family":"Liu","sequence":"additional","affiliation":[{"name":"Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated Hospital, Sun Yat-sen University","place":["Guangzhou, Guangdong, 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