TGF-β3 promotes vascular normalization of prostate cancer to potentiate immunotherapy and chemotherapy
Abstract 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 regulato...
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Springer
2025-07-01
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| Series: | Cancer Immunology, Immunotherapy |
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| Online Access: | https://doi.org/10.1007/s00262-025-04103-2 |
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| author | 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 |
| author_facet | 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 |
| author_sort | Qiliang Teng |
| collection | DOAJ |
| description | Abstract 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. |
| format | Article |
| id | doaj-art-554cadfb7d6a43cdb586fa8a8a3de8c3 |
| institution | Kabale University |
| issn | 1432-0851 |
| language | English |
| publishDate | 2025-07-01 |
| publisher | Springer |
| record_format | Article |
| series | Cancer Immunology, Immunotherapy |
| spelling | doaj-art-554cadfb7d6a43cdb586fa8a8a3de8c32025-08-20T03:42:53ZengSpringerCancer Immunology, Immunotherapy1432-08512025-07-0174811710.1007/s00262-025-04103-2TGF-β3 promotes vascular normalization of prostate cancer to potentiate immunotherapy and chemotherapyQiliang Teng0Niu Wang1Hanqi Lei2Tongyu Tong3Yupeng Guan4Mengjun Huang5Fei Cao6Bin Xu7Jia Yang8Yimian Huo9Wenping Chen10Ran Bi11Xuanqi Wang12Zhenyu Wang13Fu-Ying Tian14Bo Zhao15Jun Pang16Department of Urology, Kidney and Urology Center, Pelvic Floor Disorders Center, The Seventh Affiliated Hospital, Shenzhen Campus, Sun Yat-sen UniversityMolecular Cancer Research Center, School of Medicine, Shenzhen Campus of Sun Yat-sen UniversityDepartment of Urology, Kidney and Urology Center, Pelvic Floor Disorders Center, The Seventh Affiliated Hospital, Shenzhen Campus, Sun Yat-sen UniversityDepartment of Urology, Kidney and Urology Center, Pelvic Floor Disorders Center, The Seventh Affiliated Hospital, Shenzhen Campus, Sun Yat-sen UniversityDepartment of Urology, Kidney and Urology Center, Pelvic Floor Disorders Center, The Seventh Affiliated Hospital, Shenzhen Campus, Sun Yat-sen UniversityDepartment of Urology, Kidney and Urology Center, Pelvic Floor Disorders Center, The Seventh Affiliated Hospital, Shenzhen Campus, Sun Yat-sen UniversityDepartment of Urology, Kidney and Urology Center, Pelvic Floor Disorders Center, The Seventh Affiliated Hospital, Shenzhen Campus, Sun Yat-sen UniversityDepartment of Urology, Kidney and Urology Center, Pelvic Floor Disorders Center, The Seventh Affiliated Hospital, Shenzhen Campus, Sun Yat-sen UniversityMolecular Cancer Research Center, School of Medicine, Shenzhen Campus of Sun Yat-sen UniversityMolecular Cancer Research Center, School of Medicine, Shenzhen Campus of Sun Yat-sen UniversityMolecular Cancer Research Center, School of Medicine, Shenzhen Campus of Sun Yat-sen UniversitySchool of Medicine, Shenzhen Campus of Sun Yat-sen University, Sun Yat-sen UniversitySchool of Medicine, Shenzhen Campus of Sun Yat-sen University, Sun Yat-sen UniversitySchool of Medicine, Shenzhen Campus of Sun Yat-sen University, Sun Yat-sen UniversitySchool of Public Health, Southern Medical UniversityMolecular Cancer Research Center, School of Medicine, Shenzhen Campus of Sun Yat-sen UniversityDepartment of Urology, Kidney and Urology Center, Pelvic Floor Disorders Center, The Seventh Affiliated Hospital, Shenzhen Campus, Sun Yat-sen UniversityAbstract 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.https://doi.org/10.1007/s00262-025-04103-2Prostate cancerTGF-β3Vascular normalizationTumor microenvironment |
| spellingShingle | 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 TGF-β3 promotes vascular normalization of prostate cancer to potentiate immunotherapy and chemotherapy Cancer Immunology, Immunotherapy Prostate cancer TGF-β3 Vascular normalization Tumor microenvironment |
| title | TGF-β3 promotes vascular normalization of prostate cancer to potentiate immunotherapy and chemotherapy |
| title_full | TGF-β3 promotes vascular normalization of prostate cancer to potentiate immunotherapy and chemotherapy |
| title_fullStr | TGF-β3 promotes vascular normalization of prostate cancer to potentiate immunotherapy and chemotherapy |
| title_full_unstemmed | TGF-β3 promotes vascular normalization of prostate cancer to potentiate immunotherapy and chemotherapy |
| title_short | TGF-β3 promotes vascular normalization of prostate cancer to potentiate immunotherapy and chemotherapy |
| title_sort | tgf β3 promotes vascular normalization of prostate cancer to potentiate immunotherapy and chemotherapy |
| topic | Prostate cancer TGF-β3 Vascular normalization Tumor microenvironment |
| url | https://doi.org/10.1007/s00262-025-04103-2 |
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