文献类型：期刊文献

英文题名：Caveolin-1 drives immunosuppression in esophageal squamous cell carcinoma by enhancing exosome secretion and macrophage M2 polarization via inhibition of MVB autophagic degradation

作者：Zhai, Ke-Rong[1,2,3,4];Zhao, Pei-Lin[2];Wang, Zi-Han;Feng, Hai-Ming[1,2,3,4];Li, Zhen-Qing[1,2,3,4];Huang, Hui-Rong[1,2,3,4];Yang, Ning[1,2,3,4];Su, Zhi-Peng[1,2,3,4];Cui, Bai-Qiang[1,2,3,4];Song, Tie-Niu[1,2];Li, Bin[1,2,3,4]

第一作者：Zhai, Ke-Rong

通信作者：Li, B[1];Li, B[2];Li, B[3];Li, B[4]

机构：[1]Lanzhou Univ, Clin Med Sch 2, Dept Thorac Surg, Lanzhou 730030, Peoples R China;[2]Gansu Univ Chinese Med, Clin Med Coll 1, Lanzhou 730000, Peoples R China;[3]Lanzhou Univ, Hosp 2, Dept Thorac Surg, 82 Cuiyingmen, Lanzhou 730030, Gansu, Peoples R China;[4]Lanzhou Univ, Clin Med Sch, 82 Cuiyingmen, Lanzhou 730030, Gansu, Peoples R China

第一机构：Lanzhou Univ, Clin Med Sch 2, Dept Thorac Surg, Lanzhou 730030, Peoples R China

通信机构：[1]corresponding author), Lanzhou Univ, Clin Med Sch 2, Dept Thorac Surg, Lanzhou 730030, Peoples R China;[2]corresponding author), Gansu Univ Chinese Med, Clin Med Coll 1, Lanzhou 730000, Peoples R China;[3]corresponding author), Lanzhou Univ, Hosp 2, Dept Thorac Surg, 82 Cuiyingmen, Lanzhou 730030, Gansu, Peoples R China;[4]corresponding author), Lanzhou Univ, Clin Med Sch, 82 Cuiyingmen, Lanzhou 730030, Gansu, Peoples R China.|[10735]甘肃中医药大学;

年份：2026

卷号：24

期号：1

外文期刊名：JOURNAL OF TRANSLATIONAL MEDICINE

收录：;Scopus(收录号：2-s2.0-105031835214);WOS:【SCI-EXPANDED(收录号:WOS:001706240000001)】；

基金：This study was supported by the National Natural Science Foundation of China (No. 82060428), the Science and Technology Key Research and Development Program of Gansu Province (No. 20YF3FA032), and the Key Talent Project of Gansu Province (No. 2021RCXM062).

语种：英文

外文关键词：Esophageal squamous cell carcinoma; Caveolin-1; Exosomes; M2 macrophage polarization; Tumor microenvironment

摘要：Background Exosomes are pivotal mediators of molecular transfer and intercellular communication, orchestrating interactions between tumor cells and the tumor microenvironment (TME). However, the impact of exosomes derived from esophageal squamous cell carcinoma (ESCC) on macrophages and the mechanisms regulating their secretion remain poorly understood. Methods in vitro experiments were performed to evaluate the effects of ESCC-derived exosomes on macrophage polarization. Proteomics, bioinformatics analyses, and functional validation were employed to identify key molecules regulating exosome secretion. Stable knockdown cell lines for the candidate molecules, together with co-culture assays, were used to evaluate their effects on exosome secretion and macrophage polarization. Western blotting, transmission electron microscopy, and immunofluorescence were conducted to investigate the underlying mechanisms. Results ESCC-derived exosomes induced macrophage polarization toward the M2 phenotype in a dose-dependent manner. Functional assays identified caveolin-1 (CAV1) as a critical regulator of exosome secretion. Knockdown of CAV1 markedly reduced exosome release from ESCC cells without affecting multivesicular body (MVB) biogenesis, exosome morphology, or size distribution. CAV1 knockdown had little effect on exosome cargo composition. Moreover, it impaired the capacity of these exosomes to induce M2 polarization in macrophages, consequently enhancing CD8(+) T cell proliferation and cytotoxicity. Re-expression of CAV1 restored both exosome secretion and the ability of macrophages to undergo M2 polarization. Mechanistically, CAV1 maintains basal exosome secretion by inhibiting autophagy via sustaining PI3K/AKT/mTOR pathway activity, thereby reducing MVB-autophagic vacuole (AV) fusion and degradation. In vivo, CAV1 knockdown suppressed tumor growth in mouse xenograft models and decreased M2 macrophage infiltration. Analysis of clinical samples further confirmed that CAV1 is highly expressed in ESCC tissues and correlates with increased M2 macrophage infiltration and poor patient prognosis. Conclusion CAV1 regulates exosome secretion in ESCC cells by inhibiting autophagy, mediates macrophage M2 polarization, and promotes the formation of an immunosuppressive TME. These findings highlight the crucial role of CAV1 in tumor immune evasion and suggest it as a potential therapeutic target for ESCC immunotherapy. [GRAPHICS]