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<p>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<sup>+</sup> T cell exhaustion. Mechanistically, STK31 induced CD8<sup>+</sup> 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.</p>

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

  • 期刊论文

  • 发表日期：

    2025年3月1日

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  • Shasha Li,
  • Jiaming Lin,
  • Liu Huang,
  • Shaojie Hu,
  • Mingwei Wang,
  • Wei Sun,
  • Shuguo Sun

摘要

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.