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Background <p>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.</p> Methods in vitro <p>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.</p> Results <p>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<sup>+</sup> 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.</p> Conclusion <p>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.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年2月4日

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  • Ke-Rong Zhai,
  • Pei-Lin Zhao,
  • Zi-Han Wang,
  • Hai-Ming Feng,
  • Zhen-Qing Li,
  • Hui-Rong Huang,
  • Ning Yang,
  • Zhi-Peng Su,
  • Bai-Qiang Cui,
  • Tie-Niu Song,
  • Bin Li

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.