{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,8,28]],"date-time":"2025-08-28T00:05:48Z","timestamp":1756339548348,"version":"3.44.0"},"reference-count":13,"publisher":"BMJ","issue":"8","license":[{"start":{"date-parts":[[2025,8,27]],"date-time":"2025-08-27T00:00:00Z","timestamp":1756252800000},"content-version":"unspecified","delay-in-days":26,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100021171","name":"Guangdong Basic and Applied Basic Research Foundation","doi-asserted-by":"crossref","award":["2023A1515111183"],"award-info":[{"award-number":["2023A1515111183"]}],"id":[{"id":"10.13039\/501100021171","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100001809","name":"National Nature Science Foundation of China","doi-asserted-by":"crossref","award":["82200612"],"award-info":[{"award-number":["82200612"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":["bmj.com"],"crossmark-restriction":true},"short-container-title":["J Immunother Cancer"],"accepted":{"date-parts":[[2025,8,15]]},"published-print":{"date-parts":[[2025,8]]},"abstract":"<jats:p>Pancreatic ductal adenocarcinoma (PDAC) remains one of the deadliest malignancies, characterized by a profoundly immunosuppressive tumor microenvironment and resistance to immunotherapy. Obesity, a modifiable risk factor that increases PDAC incidence, exacerbates this immune evasion through metabolic inflammation and adipokine-driven signaling. Recent studies have implicated CXC chemokines, particularly CXCL5, as central mediators in shaping the immune landscape of PDAC. In a pivotal study, Walsh <jats:italic>et al<\/jats:italic> delineated a novel mechanism wherein adipocyte-derived cytokines (interleukin-1\u03b2 and tumor necrosis factor) induce tumor-derived CXCL5 expression, thereby promoting myeloid-driven immunosuppression in obese PDAC models. Their findings demonstrated that CXCL5 ablation enhances CD8<jats:sup>+<\/jats:sup> T-cell infiltration yet paradoxically increases monocytic myeloid-derived suppressor cell accumulation and arginase-1 expression, underscoring the complexity of chemokine signaling. Notably, only combinatorial targeting of CXCL5 and programmed cell death protein-1 yields therapeutic benefit, emphasizing the necessity of multiaxis interventions. This commentary synthesizes the mechanistic insights and translational implications of these findings, highlighting CXCL5 as a pivotal node linking metabolic dysfunction to immune resistance and a promising target for combinatorial immunotherapy in PDAC.<\/jats:p>","DOI":"10.1136\/jitc-2025-012566","type":"journal-article","created":{"date-parts":[[2025,8,27]],"date-time":"2025-08-27T17:20:33Z","timestamp":1756315233000},"page":"e012566","update-policy":"https:\/\/doi.org\/10.1136\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":0,"title":["Dual-faced CXCL5 holds the key to unlocking immunotherapy in obese pancreatic cancer"],"prefix":"10.1136","volume":"13","clinical-trial-number":[{"clinical-trial-number":"nct02001974","registry":"10.18810\/clinical-trials-gov"}],"author":[{"given":"Liping","family":"Liang","sequence":"first","affiliation":[{"name":"Department of Gastroenterology and Hepatology, Guangzhou Key Laboratory of Digestive Diseases, Guangzhou Digestive Disease 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