{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,9]],"date-time":"2026-11-09T21:05:43Z","timestamp":1794258343477,"version":"4.9.0"},"reference-count":145,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,7,7]],"date-time":"2026-07-07T00:00:00Z","timestamp":1783382400000},"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>\n                    Pancreatic ductal adenocarcinoma (PDAC) is among the most lethal cancers and is characterised by an immunologically \u201ccold\u201d microenvironment that limits responses to immunotherapy. This review focuses on interleukin-6 (IL-6), produced by stromal and immune cells as well as PDAC cells, as a central driver of immune evasion via JAK\u2013STAT3 signalling. We outline how SOCS3 silencing in tumour cells inverts the IL-6\u2013IDO relationship seen in dendritic cells, generating an autocrine IDO\u2013Kyn\u2013AhR\u2013IL-6\u2013STAT3 feedforward loop. We further describe IL-6\u2013mediated stabilisation of PD-L1, sustained PD-1 expression on CD8\n                    <jats:sup>+<\/jats:sup>\n                    T cells, and ST6GAL1-driven hypersialylation that activates Siglec glyco-immune checkpoints. In addition, we examine the IL-6\u2013Blimp-1\u2013IL-10 axis and its reprogramming of dendritic cell and T cell compartments. Given the repeated failure of IL-6(R) blockade in clinical trials, we contrast these outcomes with the more encouraging signals from RAS-targeted strategies. We propose rational IL-6\u2013integrated combinations with upstream oncogenic targeting may represent an unrealised frontier for this disease.\n                  <\/jats:p>","DOI":"10.3389\/fimmu.2026.1885999","type":"journal-article","created":{"date-parts":[[2026,7,7]],"date-time":"2026-07-07T04:22:27Z","timestamp":1783398147000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":1,"title":["IL-6 as a central driver of immune evasion in PDAC: from IDO-mediated tolerance to multi-pathway immunosuppression"],"prefix":"10.3389","volume":"17","author":[{"given":"Joyce","family":"Wang","sequence":"first","affiliation":[{"name":"Singapore Immunology Network (SIgN), Agency for Science, Technology and Research (ASTAR)","place":["Singapore, Singapore"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jolene Su Yi","family":"Tan","sequence":"additional","affiliation":[{"name":"Department of Neurology, Tan Tock Seng 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