Authors
Lele Zhang, Liangdong Sun, Shengnan Duan, Yilv Yan, Jinyi Song, Linghui Xia, Huansha Yu, Jijun Sun, Junjie Hu, Di Wang, Lu Han, Jue Wang, Yan Chen, Hu Zhou, Chen Wang, Haiyang Hu, Ming Ding, Peng Zhang
Published in
Science advances. Volume 12. Issue 33. Pages eadz0583. Aug 14, 2026. Epub Aug 12, 2026.
Abstract
Pulmonary large-cell neuroendocrine carcinoma (LCNEC) is a rare yet highly aggressive subtype of non-small cell lung carcinoma (NSCLC) with limited therapeutic options. We conduct a comprehensive proteogenomic analysis of LCNEC using tumors and paired normal adjacent tissues from 107 patients (81 pure LCNEC and 26 combined LCNEC). APOBEC mutational signatures strongly correlate processes of tumor initiation and immune suppression, and KEAP1 mutations correlate with metabolic reprogramming in LCNEC combined with NSCLC. A conflicting relationship is observed between neuroendocrine and immune phenotypes. We identify three LCNEC subtypes with unique prognosis features, microenvironment dysregulation, genetic alterations, and potential therapeutic targets. Interleukin-33 (IL-33) emerges as a critical therapeutic biomarker associated with enhanced T cell infiltration and antitumor activity. We further optimize recombinant IL-33 (rIL33) with site-directed mutagenesis and develop PEGylated rIL33, demonstrating its prolonged circulation time in cynomolgus monkeys and superior immune agonist activity in mouse models. Overall, this study offers insights into LCNEC biology and provides promising innovative immunoagonist therapy strategies for lung cancer.
PMID:
42585338
Bibliographic data and abstract were imported from PubMed on 13 Aug 2026.
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