PROCR diminishes the efficacy of radiation by impairing T-cell-mediated antitumour immunity

Weipeng Chen, Chuqing Zhang, Zhe Li, Zhimin Xu, Cong Ding, Jiawei Wu, Hanmiao Wei, Zhenji Deng, Tingxiang He, Liufen Long, Yanping Mao (), Jun Ma () and Xiaoyu Liang ()
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Weipeng Chen: Sun Yat-sen University Cancer Center
Chuqing Zhang: Sun Yat-sen University Cancer Center
Zhe Li: Sun Yat-sen University Cancer Center
Zhimin Xu: Sun Yat-sen University Cancer Center
Cong Ding: Sun Yat-sen University Cancer Center
Jiawei Wu: Sun Yat-sen University Cancer Center
Hanmiao Wei: Sun Yat-sen University Cancer Center
Zhenji Deng: Sun Yat-sen University Cancer Center
Tingxiang He: Sun Yat-sen University Cancer Center
Liufen Long: Sun Yat-sen University Cancer Center
Yanping Mao: Sun Yat-sen University Cancer Center
Jun Ma: Sun Yat-sen University Cancer Center
Xiaoyu Liang: Sun Yat-sen University Cancer Center

Nature Communications, 2025, vol. 16, issue 1, 1-18

Abstract: Abstract T cell dependent anti-tumour immunity reprogrammed by radiotherapy is critical for its efficacy. However, the mechanisms by which tumour cells hinder this process remain poorly understood. Here, we show that tumour cells expressing protein C receptor (PROCR) dampen antitumour immunity by promoting the production of interleukin-6 (IL-6), which inhibits the differentiation of T helper 1 (Th1) cells and suppresses the function of CD8+ T cells. We also demonstrate that radiation therapy enhances PROCR expression by reducing its selective autophagic degradation through the modulation of p62 phosphorylation, a process governed by mTORC1 signalling. This suggests that PROCR upregulation is an intrinsic cellular response to radiation. Targeting PROCR or IL-6 improves the efficacy of radiotherapy in preclinical models, including humanized mice and immunocompetent mice. In patients with nasopharyngeal carcinoma, higher PROCR expression correlates with reduced Th1 cell infiltration and worse functional state of CD8+ T cells. Meanwhile, elevated levels of PROCR or IL-6 are associated with reduced responsiveness to radiotherapy. These findings identify PROCR as a key immunosuppressive factor linked to radiotherapy resistance and highlight its potential as a therapeutic target to enhance treatment outcomes.

Date: 2025
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DOI: 10.1038/s41467-025-62558-4

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