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

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.