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<p>Sphingosine-1-phosphate (S1P) has been implicated in promoting breast cancer progression, but its role in fostering an immunosuppressive microenvironment remains largely unexplored. In our study, co-culturing CD8 T cells with S1P-treated MCF7 cells significantly reduced CD8 T cell proliferation, an effect reversed by inhibiting exosome biogenesis. S1P treatment enhanced exosome release from breast cancer cells, with increased levels of TGFBR2 detected on the exosome surface. These S1P-induced exosomes promoted CD8 T cell exhaustion. Silencing TGFBR2 in cancer cells or treating with anti-TGFBR2 antibodies mitigated CD8 T cell exhaustion thereby highlighting the pivotal role of TGFBR2. Further investigation revealed that S1P drives the production of TGFBR2-loaded exosomes by activating the S1P1 receptor and engaging the AKT-Rab27a axis to facilitate exosome release. Additionally, S1P upregulates TGFBR2 expression and stability through the S1P1-LEF1 and S1P1-CREB1-USP8 pathways respectively, thereby contributing to immune suppression. In vivo administration of exosomes derived from S1P-treated murine breast cancer cells in a breast cancer allograft model markedly promoted tumor growth and heightened CD8 T cell exhaustion, whereas exosomes from TGFBR2-silenced, S1P-treated cells exerted the reverse effect, underscoring the pivotal role of the S1P-TGFBR2 axis in modulating the tumor microenvironment. These findings suggest that targeting the S1P-TGFBR2 pathway could enhance antitumor immunity in breast cancer.</p>

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Sphingosine-1-phosphate promotes CD8 T cell exhaustion in breast cancer via exosomal transfer of TGFBR2

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年3月23日

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  • Avinandan Bhoumick,
  • Arnab Ghosh,
  • Arpana Singh,
  • Subhasis Mandal,
  • Tanvi Agarwal,
  • Rima Halder,
  • Biswajit Das,
  • Soma Mukhopadhyay,
  • Prosenjit Sen

摘要

Sphingosine-1-phosphate (S1P) has been implicated in promoting breast cancer progression, but its role in fostering an immunosuppressive microenvironment remains largely unexplored. In our study, co-culturing CD8 T cells with S1P-treated MCF7 cells significantly reduced CD8 T cell proliferation, an effect reversed by inhibiting exosome biogenesis. S1P treatment enhanced exosome release from breast cancer cells, with increased levels of TGFBR2 detected on the exosome surface. These S1P-induced exosomes promoted CD8 T cell exhaustion. Silencing TGFBR2 in cancer cells or treating with anti-TGFBR2 antibodies mitigated CD8 T cell exhaustion thereby highlighting the pivotal role of TGFBR2. Further investigation revealed that S1P drives the production of TGFBR2-loaded exosomes by activating the S1P1 receptor and engaging the AKT-Rab27a axis to facilitate exosome release. Additionally, S1P upregulates TGFBR2 expression and stability through the S1P1-LEF1 and S1P1-CREB1-USP8 pathways respectively, thereby contributing to immune suppression. In vivo administration of exosomes derived from S1P-treated murine breast cancer cells in a breast cancer allograft model markedly promoted tumor growth and heightened CD8 T cell exhaustion, whereas exosomes from TGFBR2-silenced, S1P-treated cells exerted the reverse effect, underscoring the pivotal role of the S1P-TGFBR2 axis in modulating the tumor microenvironment. These findings suggest that targeting the S1P-TGFBR2 pathway could enhance antitumor immunity in breast cancer.