{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,19]],"date-time":"2026-10-19T14:23:12Z","timestamp":1792419792600,"version":"4.5.0"},"reference-count":88,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,3,18]],"date-time":"2026-03-18T00:00:00Z","timestamp":1773792000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["U21A20374, 82173091, 81701630"],"award-info":[{"award-number":["U21A20374, 82173091, 81701630"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100007219","name":"Natural Science Foundation of Shanghai Municipality","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100007219","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:p>\n                    Pancreatic ductal adenocarcinoma (PDAC) remains one of the deadliest cancers, with immunotherapy yielding &amp;lt;10% objective response rates (ORR) due to its profoundly immunosuppressive tumor microenvironment (TME). This review integrates preclinical and clinical evidence (2018-2026) to dissect how stromal desmoplasia, myeloid dominance, T-cell exclusion, and impaired antigen presentation converge to form an immune-privileged niche. Key resistance pathways, including cGAS-STING, Hedgehog, and NF-\u03baB, are discussed alongside emerging strategies such as CAR-T cells, mRNA neoantigen vaccines, STING agonists, CD39\/CD73 blockade, and cDC1-based vaccines. Despite incremental progress, durable responses remain rare, emphasizing that single-target interventions are insufficient. We propose a \u201c3D+R\u201d framework, De-desmoplasia, De-adenosine,\n                    <jats:italic>De-novo<\/jats:italic>\n                    antigen, and Rational sequencing, to guide multidimensional, biomarker-driven immunotherapy design. Approaches such as timed cDC1 vaccination, patient-tuned STING agonism, and metabolic checkpoint inhibition exemplify how PDAC\u2019s immune-desert phenotype may be reshaped toward an immune-reactive state. Conceptualizing PDAC as a dynamic immune ecosystem rather than a mutation-driven entity may ultimately transform sporadic responses into durable and predictable clinical benefit.\n                  <\/jats:p>","DOI":"10.3389\/fimmu.2026.1782960","type":"journal-article","created":{"date-parts":[[2026,3,18]],"date-time":"2026-03-18T06:57:02Z","timestamp":1773817022000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":5,"title":["Overcoming multidimensional immunotherapy resistance in PDAC: from microenvironment to clinic"],"prefix":"10.3389","volume":"17","author":[{"given":"Jin","family":"Yan","sequence":"first","affiliation":[{"name":"Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center","place":["Shanghai, China"]},{"name":"Department of Oncology, Shanghai Medical College, Fudan University","place":["Shanghai, China"]},{"name":"Shanghai Pancreatic Cancer Institute","place":["Shanghai, China"]},{"name":"Shanghai Key Laboratory of Precision Medicine for Pancreatic Cancer","place":["Shanghai, China"]},{"name":"Pancreatic Cancer Institute, Fudan University","place":["Shanghai, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Huiyi","family":"Ou","sequence":"additional","affiliation":[{"name":"Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center","place":["Shanghai, China"]},{"name":"Department of Oncology, Shanghai Medical College, Fudan University","place":["Shanghai, China"]},{"name":"Shanghai Pancreatic Cancer Institute","place":["Shanghai, China"]},{"name":"Shanghai Key Laboratory of Precision Medicine for Pancreatic Cancer","place":["Shanghai, China"]},{"name":"Pancreatic Cancer Institute, Fudan University","place":["Shanghai, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shuai","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center","place":["Shanghai, China"]},{"name":"Department of Oncology, Shanghai Medical College, Fudan University","place":["Shanghai, China"]},{"name":"Shanghai Pancreatic Cancer Institute","place":["Shanghai, China"]},{"name":"Shanghai Key Laboratory of Precision Medicine for Pancreatic Cancer","place":["Shanghai, China"]},{"name":"Pancreatic Cancer Institute, Fudan University","place":["Shanghai, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kaizhou","family":"Jin","sequence":"additional","affiliation":[{"name":"Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center","place":["Shanghai, China"]},{"name":"Department of Oncology, Shanghai Medical College, Fudan University","place":["Shanghai, China"]},{"name":"Shanghai Pancreatic Cancer Institute","place":["Shanghai, China"]},{"name":"Shanghai Key Laboratory of Precision Medicine for Pancreatic Cancer","place":["Shanghai, China"]},{"name":"Pancreatic Cancer Institute, Fudan University","place":["Shanghai, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xianjun","family":"Yu","sequence":"additional","affiliation":[{"name":"Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center","place":["Shanghai, China"]},{"name":"Department of Oncology, Shanghai Medical College, Fudan University","place":["Shanghai, China"]},{"name":"Shanghai Pancreatic Cancer Institute","place":["Shanghai, China"]},{"name":"Shanghai Key Laboratory of Precision Medicine for Pancreatic Cancer","place":["Shanghai, China"]},{"name":"Pancreatic Cancer Institute, Fudan University","place":["Shanghai, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Weiding","family":"Wu","sequence":"additional","affiliation":[{"name":"Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center","place":["Shanghai, China"]},{"name":"Department of Oncology, Shanghai Medical College, Fudan University","place":["Shanghai, China"]},{"name":"Shanghai Pancreatic Cancer Institute","place":["Shanghai, China"]},{"name":"Shanghai Key Laboratory of Precision Medicine for Pancreatic Cancer","place":["Shanghai, China"]},{"name":"Pancreatic Cancer Institute, Fudan University","place":["Shanghai, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,3,18]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1038\/s41571-020-0363-5","article-title":"The tumour microenvironment in pancreatic cancer\u2014clinical challenges and opportunities","volume":"17","author":"Ho","year":"2020","journal-title":"Nat Rev Clin Oncol"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.4251\/wjgo.v12.i2.173","article-title":"Pancreatic ductal adenocarcinoma: treatment hurdles, tumor microenvironment and immunotherapy","volume":"12","author":"Sarantis","year":"2020","journal-title":"World J Gastrointest 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