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Background <p>Prostate cancer (PCa) has previously been established as a cold tumor with highly complex tumor environment. Transforming growth factor (TGF)-β1 plays pro-oncogenic roles in PCa. TGF-β3, another isoform of the TGF-β family, is reported to have different and even opposite regulatory roles to TGF-β1. However, the effect of TGF-β3 in PCa has not been elucidated.</p> Methods <p>TGF-β3 expression and its association with multiple clinicopathological characteristics were analyzed immunohistochemically in human PCa specimens. The antitumor effect of TGF-β3 and its combination with immunochemotherapy was observed by subcutaneous xenograft tumor model. RNA-seq of mouse tumor tissues identified differentially expressed genes (DEGs) that were enriched in vascular biological processes. The angiogenesis effect of TGF-β3 was evaluated using tube formation assay. Hypoxic area, NG2<sup>+</sup> pericytes, Col IV<sup>+</sup> basement membrane, adhesion molecules and immune cells were analyzed by immunofluorescence. Vascular permeability was measured by Evans blue staining. The flow cytometry was conducted to examine the composition of tumor-infiltrating CD8<sup>+</sup> T cells.</p> Results <p>Low TGF-β3 expression in prostate cancer (PCa) was correlated with higher Gleason scores and pathological T stage. While intratumoral TGF-β3 injection demonstrated antitumor effects in vivo, it did not directly affect PCa cell proliferation, migration or invasion in vitro. GO analysis revealed significant enrichment of DEGs in vascular-related biological process. TGF-β3 treatment normalized tumor vascular architecture and reduced vascular leakage. This vascular normalization upregulated endothelial adhesion molecules and enhanced CD8<sup>+</sup> T cell infiltration, suppressing tumor growth. Critically, TGF-β3-induced vascular normalization synergized with anti-PD-L1 immunotherapy or paclitaxel chemotherapy, enhancing CD8<sup>+</sup> T cell or drug infiltration and significantly boosting therapeutic efficacy.</p> Conclusions <p>TGF-β3 potentially acts as a protective factor in PCa by promoting vascular normalization and remodeling of the tumor environment, which facilitates infiltration of CD8<sup>+</sup> T cells or drugs, significantly enhancing their antitumor effects.</p>

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TGF-β3 promotes vascular normalization of prostate cancer to potentiate immunotherapy and chemotherapy

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年7月12日

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  • Qiliang Teng,
  • Niu Wang,
  • Hanqi Lei,
  • Tongyu Tong,
  • Yupeng Guan,
  • Mengjun Huang,
  • Fei Cao,
  • Bin Xu,
  • Jia Yang,
  • Yimian Huo,
  • Wenping Chen,
  • Ran Bi,
  • Xuanqi Wang,
  • Zhenyu Wang,
  • Fu-Ying Tian,
  • Bo Zhao,
  • Jun Pang

摘要

Background

Prostate cancer (PCa) has previously been established as a cold tumor with highly complex tumor environment. Transforming growth factor (TGF)-β1 plays pro-oncogenic roles in PCa. TGF-β3, another isoform of the TGF-β family, is reported to have different and even opposite regulatory roles to TGF-β1. However, the effect of TGF-β3 in PCa has not been elucidated.

Methods

TGF-β3 expression and its association with multiple clinicopathological characteristics were analyzed immunohistochemically in human PCa specimens. The antitumor effect of TGF-β3 and its combination with immunochemotherapy was observed by subcutaneous xenograft tumor model. RNA-seq of mouse tumor tissues identified differentially expressed genes (DEGs) that were enriched in vascular biological processes. The angiogenesis effect of TGF-β3 was evaluated using tube formation assay. Hypoxic area, NG2+ pericytes, Col IV+ basement membrane, adhesion molecules and immune cells were analyzed by immunofluorescence. Vascular permeability was measured by Evans blue staining. The flow cytometry was conducted to examine the composition of tumor-infiltrating CD8+ T cells.

Results

Low TGF-β3 expression in prostate cancer (PCa) was correlated with higher Gleason scores and pathological T stage. While intratumoral TGF-β3 injection demonstrated antitumor effects in vivo, it did not directly affect PCa cell proliferation, migration or invasion in vitro. GO analysis revealed significant enrichment of DEGs in vascular-related biological process. TGF-β3 treatment normalized tumor vascular architecture and reduced vascular leakage. This vascular normalization upregulated endothelial adhesion molecules and enhanced CD8+ T cell infiltration, suppressing tumor growth. Critically, TGF-β3-induced vascular normalization synergized with anti-PD-L1 immunotherapy or paclitaxel chemotherapy, enhancing CD8+ T cell or drug infiltration and significantly boosting therapeutic efficacy.

Conclusions

TGF-β3 potentially acts as a protective factor in PCa by promoting vascular normalization and remodeling of the tumor environment, which facilitates infiltration of CD8+ T cells or drugs, significantly enhancing their antitumor effects.