Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

STK31 drives tumor immune evasion through STAT3-IL-6 mediated CD8+ T cell exhaustion

Oncogene volume 44, pages 1452–1462 (2025)Cite this article

Subjects

Abstract

Dysregulations in protein kinases significantly contribute to the initiation, progression, and drug resistance in non-small cell lung cancer (NSCLC). Identification of novel oncogenic drivers within the human kinome is crucial for targeted therapy. In this study, we conducted a comprehensive analysis of the TCGA database and literature, pinpointing 16 candidate genes in lung cancer exhibiting frequent dysregulation and limited research. Our functional analysis revealed Serine/threonine kinase 31 (STK31) as a key player in driving tumor growth, in immune-competent mice, with minimal impact in nude mice. Further investigations unveiled upregulation of STK31 led to CD8+ T cell exhaustion. Mechanistically, STK31 induced CD8+ T cell exhaustion through the signal transducer and activator of transcription 3 (STAT3) - interleukin 6 (IL-6) signaling pathway. Direct interaction between STK31 and STAT3 activated the transcription of downstream oncogenic targets, such as IL-6, facilitating immune escape. Moreover, STK31 exhibited elevated expression levels in lung cancer tissues compared to adjacent tissues and displayed a significant correlation with poor prognosis in lung cancer patients. This study defines a critical role of STK31 in promoting immune escape through STAT3 activation, positioning it as a promising therapeutic target for lung cancer.

Access through your institution
Buy or subscribe

This is a preview of subscription content, access via your institution

Access options

Access through your institution

Buy this article

  • Purchase on SpringerLink
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: Identification of oncogenic kinase drivers of lung adenocarcinoma in immunocompetent mice model.
Fig. 2: STK31 is upregulated in lung cancer and correlated with poor survival in lung cancer patients.
Fig. 3: STK31 promotes tumor growth by tumor microenvironment.
Fig. 4: STK31 induce tumor immune escape through increased CD8+ T cells exhaustion.
Fig. 5: STK31 induces JAK-STAT pathway activations.
Fig. 6: STK31 activates JAK-STAT pathway through direct binding to STAT3.

Similar content being viewed by others

Data availability

The sequencing data of this study are available through GSA under accession number CRA016768. Other datasets during the study are available from the corresponding author upon reasonable request.

References

  1. Sung H, Ferlay J, Siegel RL, Laversanne M, Soerjomataram I, Jemal A, et al. Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2021;71:209–49.

    Article  PubMed  Google Scholar 

  2. Ferlay J, Colombet M, Soerjomataram I, Parkin DM, Pineros M, Znaor A, et al. Cancer statistics for the year 2020: an overview. Int J Cancer. 2021;149:778–89.

    Article  CAS  Google Scholar 

  3. Cao W, Chen HD, Yu YW, Li N, Chen WQ. Changing profiles of cancer burden worldwide and in China: a secondary analysis of the global cancer statistics 2020. Chin Med J Peking. 2021;134:783–91.

    Article  Google Scholar 

  4. Osmani L, Askin F, Gabrielson E, Li QK. Current WHO guidelines and the critical role of immunohistochemical markers in the subclassification of non-small cell lung carcinoma (NSCLC): moving from targeted therapy to immunotherapy. Semin Cancer Biol. 2018;52:103–9.

    Article  CAS  PubMed  Google Scholar 

  5. Nong C, Guan P, Li L, Zhang H, Hu H. Tumor immunotherapy: mechanisms and clinical applications. MedComm Oncol. 2022;1:e8.

    Article  Google Scholar 

  6. Konig D, Prince SS, Rothschild SI. Targeted therapy in advanced and metastatic non-small cell lung cancer. An update on treatment of the most important actionable oncogenic driver alterations. Cancers. 2021;13:804.

    Article  PubMed  PubMed Central  Google Scholar 

  7. Cohen P. Protein kinases - the major drug targets of the twenty-first century? Nat Rev Drug Discov. 2002;1:309–15.

    Article  CAS  PubMed  Google Scholar 

  8. Roskoski R. A historical overview of protein kinases and their targeted small molecule inhibitors. Pharm Res. 2015;100:1–23.

    Article  CAS  Google Scholar 

  9. Roskoski R. Properties of FDA-approved small molecule protein kinase inhibitors: a 2023 update. Pharm Res. 2023;187:106552.

    Article  CAS  Google Scholar 

  10. Roskoski R. Futibatinib (Lytgobi) for cholangiocarcinoma. Trends Pharm Sci. 2023;44:190–1.

    Article  CAS  PubMed  Google Scholar 

  11. Attwood MM, Fabbro D, Sokolov AV, Knapp S, Schioth HB. Trends in kinase drug discovery: targets, indications and inhibitor design. Nat Rev Drug Discov. 2021;20:839–61.

    Article  CAS  PubMed  Google Scholar 

  12. Olesen C, Nyeng P, Kalisz M, Jensen TH, Moller M, Tommerup N, et al. Global gene expression analysis in fetal mouse ovaries with and without meiosis and comparison of selected genes with meiosis in the testis. Cell Tissue Res. 2007;328:207–21.

    Article  CAS  PubMed  Google Scholar 

  13. Bao J, Yuan S, Maestas A, Bhetwal BP, Schuster A, Yan W. Stk31 is dispensable for embryonic development and spermatogenesis in mice. Mol Reprod Dev. 2013;80:786.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Xiong J, Xing S, Dong Z, Niu L, Xu Q, Liu P, et al. STK31 regulates the proliferation and cell cycle of lung cancer cells via the Wnt/β‑catenin pathway and feedback regulation by c‑myc. Oncol Rep. 2020;43:395–404.

    CAS  PubMed  Google Scholar 

  15. Bae DH, Kim HJ, Yoon BH, Park JL, Kim M, Kim SK, et al. STK31 upregulation is associated with chromatin remodeling in gastric cancer and induction of tumorigenicity in a xenograft mouse model. Oncol Rep. 2021;45:42.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Yokoe T, Tanaka F, Mimori K, Inoue H, Ohmachi T, Kusunoki M, et al. Efficient identification of a novel cancer/testis antigen for immunotherapy using three-step microarray analysis. Cancer Res. 2008;68:1074–82.

    Article  CAS  PubMed  Google Scholar 

  17. Gao H, Cai BB, Lu ZP, Wang GF, Gao Y, Miao Y, et al. Cancer-testis gene STK31 is regulated by methylation and promotes the development of pancreatic cancer. Cancer Med. 2023;12:7273–82.

    Article  CAS  PubMed  Google Scholar 

  18. Yang P, Meng M, Zhou QS. Oncogenic cancer/testis antigens are a hallmarker of cancer and a sensible target for cancer immunotherapy. BBA-Rev Cancer. 2021;1876:188558.

    CAS  Google Scholar 

  19. Fok KL, Chung CM, Yi SQ, Jiang X, Sun X, Chen H, et al. STK31 maintains the undifferentiated state of colon cancer cells. Carcinogenesis. 2012;33:2044–53.

    Article  CAS  PubMed  Google Scholar 

  20. Yu M, Peng Z, Qin M, Liu Y, Wang J, Zhang C, et al. Interferon-gamma induces tumor resistance to anti-PD-1 immunotherapy by promoting YAP phase separation. Mol Cell. 2021;81:1216–30.e1219.

    Article  CAS  PubMed  Google Scholar 

  21. Mao Y, Sun S, Irvine KD. Role and regulation of Yap in KrasG12D-induced lung cancer. Oncotarget. 2017;8:110877–89.

    Article  PubMed  PubMed Central  Google Scholar 

  22. Wang PJ, McCarrey JR, Yang F, Page DC. An abundance of X-linked genes expressed in spermatogonia. Nat Genet. 2001;27:422–6.

    Article  PubMed  Google Scholar 

  23. Khan O, Giles JR, McDonald S, Manne S, Ngiow SF, Patel KP, et al. TOX transcriptionally and epigenetically programs CD8(+) T cell exhaustion. Nature. 2019;571:211–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Alfei F, Kanev K, Hofmann M, Wu M, Ghoneim HE, Roelli P, et al. TOX reinforces the phenotype and longevity of exhausted T cells in chronic viral infection. Nature. 2019;571:265–9.

    Article  CAS  PubMed  Google Scholar 

  25. Li YJ, Zhang CY, Martincuks A, Herrmann A, Yu H. STAT proteins in cancer: orchestration of metabolism. Nat Rev Cancer. 2023;23:115–34.

    Article  PubMed  Google Scholar 

  26. Yeh HH, Lai WW, Chen HHW, Liu HS, Su WC. Autocrine IL-6-induced Stat3 activation contributes to the pathogenesis of lung adenocarcinoma and malignant pleural effusion. Oncogene. 2006;25:4300–9.

    Article  CAS  PubMed  Google Scholar 

  27. Chang CH, Hsiao CF, Yeh YM, Chang GC, Tsai YH, Chen YM, et al. Circulating interleukin-6 level is a prognostic marker for survival in advanced nonsmall cell lung cancer patients treated with chemotherapy. Int J Cancer. 2013;132:1977–85.

    Article  CAS  PubMed  Google Scholar 

  28. Szyf M, Pakneshan P, Rabbani SA. DNA demethylation and cancer: therapeutic implications. Cancer Lett. 2004;211:133–43.

    Article  CAS  PubMed  Google Scholar 

  29. Meng H, Li GYA, Wei W, Bai YS, Feng Y, Fu M, et al. Epigenome-wide DNA methylation signature of benzo[a]pyrene exposure and their mediation roles in benzo[a]pyrene-associated lung cancer development. J Hazard Mater. 2021;416:125839.

    Article  CAS  PubMed  Google Scholar 

  30. Johnson DE, O’Keefe RA, Grandis JR. Targeting the IL-6/JAK/STAT3 signalling axis in cancer. Nat Rev Clin Oncol. 2018;15:234–48.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Wang MW, Li SS, Guo WC, Wang LL, Huang JX, Zhuo JZ, et al. CHRAC1 promotes human lung cancer growth through regulating YAP transcriptional activity. Carcinogenesis. 2021;43:264–76.

    Article  Google Scholar 

  32. Zhang H, Li S, Zhou R, Dong T, Zhang X, Yu M, et al. SRCAP complex promotes lung cancer progression by reprograming the oncogenic transcription of Hippo-YAP/TAZ signaling pathway. Cancer Lett. 2024;585:216667.

    Article  CAS  PubMed  Google Scholar 

  33. Burrack AL, Schmiechen ZC, Patterson MT, Miller EA, Spartz EJ, Rollins MR, et al. Distinct myeloid antigen-presenting cells dictate differential fates of tumor-specific CD8+ T cells in pancreatic cancer. JCI Insight. 2022;7:e151593.

    Article  PubMed  PubMed Central  Google Scholar 

  34. Zhang HX, Zhang C, Tang H, Gao SS, Sun F, Yang Y, et al. CD2-associated protein contributes to hepatitis C, virus propagation and steatosis by disrupting insulin signaling. Hepatology. 2018;68:1710–25.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We thank Dr. Yu Xue in Huazhong University of Science and Technology for the bioinformatic analysis of cancer driver genes. This research was supported by NSFC National Natural Science Foundation and Ministry of Science and Technology of China (2023YFC2307304), This study also was supported by National Natural Science Foundation of China (No. 81902853) and in part by a Foundation of Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology (2022A07).

Author information

Author notes

  1. These authors contributed equally: Shasha Li, Jiaming Lin.

Authors and Affiliations

  1. Department of Human Anatomy, Histology and Embryology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China

    Shasha Li, Jiaming Lin & Shuguo Sun

  2. Department of Histology and Embryology, Department of Basic Medicine, Changzhi Medical College, Changzhi, China

    Shasha Li

  3. Department of Oncology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China

    Liu Huang

  4. Department of Thoracic Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China

    Shaojie Hu & Wei Sun

  5. Department of Pathology, Hubei Cancer Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China

    Mingwei Wang

Authors
  1. Shasha Li
    View author publications

    Search author on:PubMed Google Scholar

  2. Jiaming Lin
    View author publications

    Search author on:PubMed Google Scholar

  3. Liu Huang
    View author publications

    Search author on:PubMed Google Scholar

  4. Shaojie Hu
    View author publications

    Search author on:PubMed Google Scholar

  5. Mingwei Wang
    View author publications

    Search author on:PubMed Google Scholar

  6. Wei Sun
    View author publications

    Search author on:PubMed Google Scholar

  7. Shuguo Sun
    View author publications

    Search author on:PubMed Google Scholar

Contributions

SS contributed to experimental design, data analysis, and wrote the manuscript. WS contributed to experimental design, provided the patient samples and wrote the manuscript. LS designed experiments, analyzed data, performed experiments, data acquisition, and manuscript preparation. JL performed experiments, data acquisition, and manuscript preparation. SH performed experiments and data acquisition. LH provided the patient samples. MW provided the patient samples.

Corresponding authors

Correspondence to Wei Sun or Shuguo Sun.

Ethics declarations

Competing interests

The authors declare no competing interests.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Li, S., Lin, J., Huang, L. et al. STK31 drives tumor immune evasion through STAT3-IL-6 mediated CD8+ T cell exhaustion. Oncogene 44, 1452–1462 (2025). https://doi.org/10.1038/s41388-024-03271-2

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41388-024-03271-2

Search

Advanced search

Quick links