Abstract
It is well established that interferon (IFN) and tumor necrosis factor (TNF) could synergistically promote antitumor toxicity and avoid resistance of antigen-negative tumors during cancer immunotherapy. The linear ubiquitin chain assembly complex (LUBAC) has been widely known to regulate receptor-interacting protein kinase-1(RIPK1) kinase activity and TNF-mediated cell death during inflammation and embryogenesis. However, whether LUBAC and RIPK1 kinase activity in tumor microenvironment could regulate antitumor immunity are still not very clear. Here, we demonstrated a cancer cell-intrinsic role of LUBAC complex in tumor microenvironment to promote tumorigenesis. Lacking LUBAC component RNF31 in B16 melanoma cells but not immune cells including macrophages or dendritic cells greatly impaired tumor growth by increasing intratumoral CD8+ T cells infiltration. Mechanistically, we found that tumor cells without RNF31 shown severe apoptosis-mediated cell death caused by TNFα/IFNγ in the tumor microenvironment. Most importantly, we found that RNF31 could limit RIPK1 kinase activity and further prevent tumor cell death in a transcription-independent manner, suggesting a crucial role of RIPK1 kinase activity in tumorigenesis. Together, our results demonstrate an essential role of RNF31 and RIPK1 kinase activity in tumorigenesis and imply that RNF31 inhibition could be harnessed to enhance antitumor toxicity during tumor immunotherapy.
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The authors declare that the data supporting the findings of this study are available within the paper and its Supplementary Information Files.
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Acknowledgements
This work was partially supported by the grant from National Key Research and Development Program of China (2019YFA0508502 to Xin Lin), National Natural Science Foundation of China (31930039, 81630058, 91942303, 31821003 to XL, and 81971469, 31670904 to XZ), and annual funding from Tsinghua University-Peking University Jointed Center for Life Sciences.
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JZ, HT and XL conceived and designed the study. JZ performed most of experiments. HT and ZZ provided help for some experiments. JZ, HT and ZZ analyzed and interpreted data. JZ, HT and XL wrote the manuscript, with all authors contributing to writing and providing feedback.
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Zhang, J., Tu, H., Zheng, Z. et al. RNF31 promotes tumorigenesis via inhibiting RIPK1 kinase-dependent apoptosis. Oncogene 42, 1585–1596 (2023). https://doi.org/10.1038/s41388-023-02669-8
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DOI: https://doi.org/10.1038/s41388-023-02669-8
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