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TLL1 knockdown attenuates prostate cancer progression by enhancing antitumor immunity

Oncogene volume 44, pages 3580–3597 (2025) Cite this article

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Abstract

Prostate cancer is one of the malignancies affecting men and contributes significantly to their increased mortality rates. Understanding the molecular mechanisms underlying the initiation and progression of prostate cancer is important for identifying potential drug targets. Here we showed that metalloproteinase TLL1 was positively associated with prostate cancer aggressiveness. Mechanistically, TLL1 promoted prostate cancer cells migration and metastasis through cleaving latent TGF-β1 to activate TGF-β signaling pathway. Moreover, LINC01179 interacted with Miz1 to attenuate TLL1 expression and LINC01179 impaired prostate cancer cell proliferation and migration ability by suppressing TLL1 expression to deactivate TGF-β signaling activity. Meanwhile, we observed that TLL1 increased the expression of PD-L1 by activating TGF-β signaling pathway and TLL1 depletion enhanced the antitumor efficacy by anti-PD-1 antibody via augmenting the infiltration proportions of CD8+ T cells in tumors. In addition, T cell-specific overexpression of TLL1 disrupted T cell development in the thymus. TLL1 overexpression in T cells accelerated RM-1 prostate tumor growth in mice by decreasing the infiltration of CD8+ T cells into tumors. Collectively, our results revealed that TLL1 may be a potential therapeutic target to alter prostate cancer progression.

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Fig. 1: TLL1 plays an oncogenic role in prostate cancer.
The alternative text for this image may have been generated using AI.
Fig. 2: TLL1 facilitated PCa cells migration and metastasis via cleaving latent TGF-β1 to enhance TGF-β signaling pathway.
The alternative text for this image may have been generated using AI.
Fig. 3: LINC01179 interacted with Miz1 to regulate TLL1 expression.
The alternative text for this image may have been generated using AI.
Fig. 4: LINC01179 attenuated PCa cells proliferation and migration by decreasing TLL1 expression and deactivating TGF-β signaling pathway.
The alternative text for this image may have been generated using AI.
Fig. 5: TLL1 suppressed SPOP expression and increased PD-L1 expression via activating TGF-β signaling pathway.
The alternative text for this image may have been generated using AI.
Fig. 6: TLL1 knockdown enhanced anti-tumor immunity in prostate cancer.
The alternative text for this image may have been generated using AI.
Fig. 7: TLL1 overexpression in T cells reduced the percentage of CD8+ T cells and promoted RM-1 prostate tumor growth in mice.
The alternative text for this image may have been generated using AI.
Fig. 8: The mechanism underlying TLL1-mediated immune evasion of PCa cells.
The alternative text for this image may have been generated using AI.

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All data generated or analyzed during this study are included in this article and Supplementary information.

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Acknowledgements

This work was funded by the National Natural Science Foundation of China (82472665), Fundamental Research Funds for the Central Universities (GK202201004, GK202505003), Natural Science Foundation of Shaanxi Province (2023-JC-YB-716), Excellent Graduate Training Program of Shaanxi Normal University (LHRCTS23091) and College Students’ Innovative Entrepreneurial Training Plan Program (202410718037). We thank Zhaoqiang Qian, Qiangqiang Wei, and Lifang Zheng from the Laboratory Animal Center of Shaanxi Normal University for their support and assistance in animal feeding, management and experiment.

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  1. These authors contributed equally: Jing-Lan Hao, Jia-Qi He, Hang Hu.

Authors and Affiliations

  1. College of Life Sciences, Shaanxi Normal University, Xi’an, China

    Jing-Lan Hao, Jia-Qi He, Hang Hu, Zi-Heng Zhu, Xi Zhao, Xiao-Yu Wu, Lan Li, Yong-Tong Ruan, Juan Yang, Xin-Yi Luo, Wang-Xue Xu, Ming Fu, Ping Gao & Xiao-Ming Dong

  2. Hansoh Bio, Rockville, MD, USA

    Kai Zhang

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Contributions

XMD, PG and KZ conceived the project, JLH, JQH, HH, ZHZ, XZ, XYW, LL, YTR, JY, XYL, WXX and MF performed the experiments. JLH and XMD performed data analysis. XMD, PG, KZ and JLH wrote the manuscript. All authors read and approved the final manuscript.

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Correspondence to Kai Zhang, Ping Gao or Xiao-Ming Dong.

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The authors confirm that all methods were performed in accordance with the relevant guidelines and regulations. Animal experiments were performed according with the approved protocols by the ethical committee of Shaanxi Normal University (Approval number: 2023-038).

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Hao, JL., He, JQ., Hu, H. et al. TLL1 knockdown attenuates prostate cancer progression by enhancing antitumor immunity. Oncogene 44, 3580–3597 (2025). https://doi.org/10.1038/s41388-025-03517-7

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