PMID- 38393971 OWN - NLM STAT- MEDLINE DCOM- 20240502 LR - 20240516 IS - 2326-6074 (Electronic) IS - 2326-6066 (Linking) VI - 12 IP - 5 DP - 2024 May 2 TI - ANXA3-Rich Exosomes Derived from Tumor-Associated Macrophages Regulate Ferroptosis and Lymphatic Metastasis of Laryngeal Squamous Cell Carcinoma. PG - 614-630 LID - 10.1158/2326-6066.CIR-23-0595 [doi] AB - Tumor-associated macrophages (TAM) induce immunosuppression in laryngeal squamous cell carcinoma (LSCC). The interaction between LSCC cells and TAMs affects the progression of laryngeal cancer through exosomes, but the underlying molecular mechanism remains unclear. Proteomics analysis of TAMs isolated from human laryngeal tumor tissues obtained from patients with confirmed lymphatic metastasis revealed an upregulation of annexin A3 (ANXA3). In TAMs, ANXA3 promoted macrophages to polarize to an M2-like phenotype by activating the AKT-GSK3beta-beta-catenin pathway. In addition, ANXA3-rich exosomes derived from TAMs inhibited ferroptosis in laryngeal cancer cells through an ATF2-CHAC1 axis, and this process was associated with lymphatic metastasis. Mechanistically, ANXA3 in exosomes inhibited the ubiquitination of ATF2, whereas ATF2 acted as a transcription factor to regulate the expression of CHAC1, thus inhibiting ferroptosis in LSCC cells. These data indicate that abnormal ANXA3 expression can drive TAM reprogramming and promote an immunosuppressive microenvironment in LSCC. Meanwhile, ANXA3-rich exosomes inhibit ferroptosis of LSCC cells and promote lymphatic metastasis, thus promoting tumor progression. CI - (c)2024 American Association for Cancer Research. FAU - Xu, Licheng AU - Xu L AUID- ORCID: 0000-0002-9447-5394 AD - Department of Otorhinolaryngology, Head and Neck Surgery, The Second Affiliated Hospital of Harbin Medical University, Harbin, China. AD - The Key Laboratory of Myocardial Ischemia, Ministry of Education, The Second Affiliated Hospital of Harbin Medical University, Harbin, China. FAU - Li, Wenjing AU - Li W AUID- ORCID: 0009-0004-9661-0483 AD - Department of Otorhinolaryngology, Head and Neck Surgery, The Second Affiliated Hospital of Harbin Medical University, Harbin, China. AD - The Key Laboratory of Myocardial Ischemia, Ministry of Education, The Second Affiliated Hospital of Harbin Medical University, Harbin, China. FAU - Liu, Danxi AU - Liu D AUID- ORCID: 0009-0006-6387-5324 AD - Department of Pancreatic and Biliary Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin, China. AD - The Key Laboratory of Hepatosplenic Surgery Ministry of Education, The First Affiliated Hospital of Harbin Medical University, Harbin, China. FAU - Cao, Jing AU - Cao J AUID- ORCID: 0000-0001-9304-3189 AD - Department of Otorhinolaryngology, Head and Neck Surgery, The Second Affiliated Hospital of Harbin Medical University, Harbin, China. FAU - Ge, Jingchun AU - Ge J AUID- ORCID: 0000-0002-3492-2156 AD - Department of Otorhinolaryngology, Head and Neck Surgery, The Second Affiliated Hospital of Harbin Medical University, Harbin, China. FAU - Liu, Xinyu AU - Liu X AUID- ORCID: 0009-0009-6702-0851 AD - Department of Otorhinolaryngology, Head and Neck Surgery, The Second Affiliated Hospital of Harbin Medical University, Harbin, China. FAU - Wang, Yue AU - Wang Y AUID- ORCID: 0009-0002-3399-899X AD - Department of Otorhinolaryngology, Head and Neck Surgery, The Second Affiliated Hospital of Harbin Medical University, Harbin, China. FAU - Teng, Yujian AU - Teng Y AUID- ORCID: 0009-0004-5054-4601 AD - Department of Otorhinolaryngology, Head and Neck Surgery, The Second Affiliated Hospital of Harbin Medical University, Harbin, China. FAU - Liu, Pengyan AU - Liu P AUID- ORCID: 0000-0003-2694-5048 AD - Department of Otorhinolaryngology, Head and Neck Surgery, The Second Affiliated Hospital of Harbin Medical University, Harbin, China. FAU - Guo, Xinyue AU - Guo X AUID- ORCID: 0009-0000-7501-4317 AD - Department of Otorhinolaryngology, Head and Neck Surgery, The Second Affiliated Hospital of Harbin Medical University, Harbin, China. FAU - He, Chen AU - He C AUID- ORCID: 0009-0003-4631-825X AD - Department of Otorhinolaryngology, Head and Neck Surgery, The Second Affiliated Hospital of Harbin Medical University, Harbin, China. AD - The Key Laboratory of Myocardial Ischemia, Ministry of Education, The Second Affiliated Hospital of Harbin Medical University, Harbin, China. FAU - Liu, Ming AU - Liu M AUID- ORCID: 0000-0002-9693-2990 AD - Department of Otorhinolaryngology, Head and Neck Surgery, The Second Affiliated Hospital of Harbin Medical University, Harbin, China. FAU - Tian, Linli AU - Tian L AUID- ORCID: 0000-0002-8934-1607 AD - Department of Otorhinolaryngology, Head and Neck Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin, China. LA - eng GR - 82082987/National Natural Science Foundation of China (NSFC)/ GR - 82273332/National Natural Science Foundation of China (NSFC)/ GR - 82173209/National Natural Science Foundation of China (NSFC)/ PT - Journal Article PT - Research Support, Non-U.S. Gov't PL - United States TA - Cancer Immunol Res JT - Cancer immunology research JID - 101614637 SB - IM MH - Animals MH - Humans MH - Male MH - Mice MH - *Annexin A3/metabolism MH - Cell Line, Tumor MH - *Exosomes/metabolism MH - *Ferroptosis MH - *Laryngeal Neoplasms/pathology/metabolism/immunology MH - Lymphatic Metastasis/immunology/pathology MH - Squamous Cell Carcinoma of Head and Neck/metabolism/pathology/immunology MH - Tumor Microenvironment/immunology MH - *Tumor-Associated Macrophages/metabolism/immunology EDAT- 2024/02/23 18:42 MHDA- 2024/05/02 06:42 CRDT- 2024/02/23 12:53 PHST- 2023/07/23 00:00 [received] PHST- 2023/12/02 00:00 [revised] PHST- 2024/02/20 00:00 [accepted] PHST- 2024/05/02 06:42 [medline] PHST- 2024/02/23 18:42 [pubmed] PHST- 2024/02/23 12:53 [entrez] AID - 734884 [pii] AID - 10.1158/2326-6066.CIR-23-0595 [doi] PST - ppublish SO - Cancer Immunol Res. 2024 May 2;12(5):614-630. doi: 10.1158/2326-6066.CIR-23-0595.