NFKB2 mediates colorectal cancer cell immune escape and metastasis in a STAT2/PD‐L1‐dependent manner
Jiwei Zhang,
Fen Ma,
Zhe Li,
Yuan Li,
Xun Sun,
Mingxu Song,
Fan Yang,
Enjiang Wu,
Xiaohui Wei,
Zhengtao Wang,
Li Yang
Affiliations
Jiwei Zhang
Shanghai Key Laboratory of Compound Chinese Medicines The MOE Key Laboratory for Standardization of Chinese Medicines Institute of Chinese Materia Medica Shanghai University of Traditional Chinese Medicine Shanghai China
Fen Ma
Shanghai Key Laboratory of Compound Chinese Medicines The MOE Key Laboratory for Standardization of Chinese Medicines Institute of Chinese Materia Medica Shanghai University of Traditional Chinese Medicine Shanghai China
Zhe Li
Academy of Integrative Medicine Shanghai University of Traditional Chinese Medicine Shanghai China
Yuan Li
Shanghai Key Laboratory of Compound Chinese Medicines The MOE Key Laboratory for Standardization of Chinese Medicines Institute of Chinese Materia Medica Shanghai University of Traditional Chinese Medicine Shanghai China
Xun Sun
Gastrointestinal Surgery Longhua Hospital Shanghai University of Traditional Chinese Medicine Shanghai China
Mingxu Song
Human Reproductive and Genetic Center Affiliated Hospital of Jiangnan University Jiangsu China
Fan Yang
Shanghai Key Laboratory of Compound Chinese Medicines The MOE Key Laboratory for Standardization of Chinese Medicines Institute of Chinese Materia Medica Shanghai University of Traditional Chinese Medicine Shanghai China
Enjiang Wu
Shanghai Key Laboratory of Compound Chinese Medicines The MOE Key Laboratory for Standardization of Chinese Medicines Institute of Chinese Materia Medica Shanghai University of Traditional Chinese Medicine Shanghai China
Xiaohui Wei
Shanghai Key Laboratory of Compound Chinese Medicines The MOE Key Laboratory for Standardization of Chinese Medicines Institute of Chinese Materia Medica Shanghai University of Traditional Chinese Medicine Shanghai China
Zhengtao Wang
Shanghai Key Laboratory of Compound Chinese Medicines The MOE Key Laboratory for Standardization of Chinese Medicines Institute of Chinese Materia Medica Shanghai University of Traditional Chinese Medicine Shanghai China
Li Yang
Shanghai Key Laboratory of Compound Chinese Medicines The MOE Key Laboratory for Standardization of Chinese Medicines Institute of Chinese Materia Medica Shanghai University of Traditional Chinese Medicine Shanghai China
Abstract This study systematically analyzed the molecular mechanism and function of nuclear factor kappa B subunit 2 (NFKB2) in colorectal cancer (CRC) to investigate the potential of NFKB2 as a therapeutic target for CRC. Various experimental techniques, including RNA sequencing, proteome chip assays, and small molecule analysis, were used to obtain a deeper understanding of the regulation of NFKB2 in CRC. The results revealed that NFKB2 was upregulated in a significant proportion of patients with advanced hepatic metastasis of CRC. NFKB2 played an important role in promoting tumor growth through CD8+ T‐cell exhaustion. Moreover, NFKB2 directly interacted with signal transducer and activator of transcription 2 (STAT2), leading to increased phosphorylation of STAT2 and the upregulation of programmed death ligand 1 (PD‐L1). Applying a small molecule inhibitor of NFKB2 (Rg5) led to a reduction in PD‐L1 expression and improved response to programmed death‐1 blockade‐based immunotherapy. In conclusion, the facilitated NFKB2‐STAT2/PD‐L1 axis may suppress immune surveillance in CRC and targeting NFKB2 may enhance the efficacy of immunotherapeutic strategies. Our results provide novel insights into the molecular mechanisms underlying the contribution of NFKB2 in CRC immune escape.
