{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,2]],"date-time":"2026-10-02T08:53:19Z","timestamp":1790931199672,"version":"4.1.0"},"reference-count":75,"publisher":"Wiley","issue":"10","license":[{"start":{"date-parts":[[2026,7,18]],"date-time":"2026-07-18T00:00:00Z","timestamp":1784332800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"},{"start":{"date-parts":[[2026,7,18]],"date-time":"2026-07-18T00:00:00Z","timestamp":1784332800000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/100007449","name":"Takeda Science Foundation","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100007449","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004398","name":"Mitsubishi Foundation","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100004398","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100005927","name":"Daiichi Sankyo Foundation of Life Science","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100005927","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100007263","name":"Astellas Foundation for Research on Metabolic Disorders","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100007263","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100007533","name":"Kobayashi Foundation for Cancer Research","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100007533","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100007428","name":"Naito Foundation","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100007428","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Cancer Science"],"published-print":{"date-parts":[[2026,10]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>Neuroendocrine neoplasms (NENs) are a heterogeneous family of epithelial malignancies that share neuroendocrine differentiation but differ in lineage origin, genomic architecture, immune contexture, and clinical behavior. Pancreatic neuroendocrine neoplasms (PanNENs) are particularly informative because well\u2010differentiated pancreatic neuroendocrine tumors (PanNETs) and poorly differentiated pancreatic neuroendocrine carcinomas (PanNECs) arise in the same organ yet follow distinct evolutionary trajectories. Despite advances in surgery, targeted therapy, chemotherapy, and peptide receptor radionuclide therapy (PRRT), advanced PanNENs remain largely incurable, and immune checkpoint blockade has shown limited and inconsistent benefit. Recent genomic, epigenomic, and immune profiling studies indicate that differentiation state and lineage programs are major organizing principles of PanNEN biology. PanNETs are typically defined by chromatin regulatory alterations, relative lineage stability, and weakly inflamed immune microenvironments, although a subset shows increased tumor\u2010associated macrophage infiltration and other immunoregulatory features linked to aggressive disease. By contrast, PanNECs are characterized by lineage instability, cell\u2010cycle dysregulation, and a more inflamed yet functionally suppressed immune context, with greater immune\u2010cell infiltration and more frequent checkpoint pathway engagement. However, these features do not necessarily indicate effective antitumor immunity, because inflammatory engagement may coexist with impaired antigen presentation, including human leukocyte antigen class I loss, tumor\u2010intrinsic immune evasion, and suppressive myeloid networks. We propose that genomic alterations, epigenetic states, and immune architectures evolve as a coupled system in PanNENs. We discuss how lineage identity shapes antigen presentation defects, immune suppression, and therapeutic vulnerability, and we outline biologically rational, precision\u2010guided strategies, including epigenetic modulation, targeting of immunosuppressive cell populations, and lineage\u2010informed therapies.<\/jats:p>","DOI":"10.1111\/cas.70466","type":"journal-article","created":{"date-parts":[[2026,7,18]],"date-time":"2026-07-18T08:42:40Z","timestamp":1784364160000},"page":"2619-2635","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Genomic Evolution and Immune Contexture With Therapeutic Relevance in Pancreatic Neuroendocrine Neoplasms"],"prefix":"10.1111","volume":"117","author":[{"ORCID":"https:\/\/orcid.org\/0009-0003-7150-9015","authenticated-orcid":false,"given":"Yohei","family":"Tabe","sequence":"first","affiliation":[{"name":"Division of Molecular Immunology, Cancer Precision Medicine Center Japanese 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