CELL INTELLIGENCE · 肿瘤细胞治疗研究
肿瘤细胞治疗研究
英文原题：Sialylation-immune-related lncRNA LINC01605 promotes tumor-infiltrating CD8(+) T cell exhaustion and malignancy of clear cell renal cell carcinoma.
Sialylation-immune-related lncRNA LINC01605 promotes tumor-infiltrating CD8(+) T cell exhaustion and malignancy of clear cell renal cell carcinoma.
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我们的研究结果揭示了唾液酸化-免疫相关 lncRNAs 在 ccRCC 免疫抑制性肿瘤微环境和癌症进展中的作用，为预测患者预后和治疗反应提供了新框架。
长链非编码RNA（lncRNA）表达失调已被证实在透明细胞肾细胞癌（ccRCC）的致瘤性中发挥关键作用。同时，唾液酸化在癌症进展和调节肿瘤免疫微环境中起着关键作用。然而，唾液酸化-免疫相关lncRNA（SIRLs）如何影响ccRCC的肿瘤免疫微环境和进展仍不清楚。
利用综合癌症数据集，我们识别了与唾液酸化和免疫调节均相关的关键lncRNA，构建了以核心基因LINC01605为中心的预后风险模型。
被归类为高风险的患者与低风险个体相比，表现出显著较差的生存结局和对anti-PD-1免疫治疗的较差反应。功能研究证实了LINC01605在增强肿瘤侵袭性和CD8 + T细胞耗竭中的作用。敲低LINC01605可降低ccRCC细胞膜中的总唾液酸水平。在机制上，LINC01605招募IGF2BP2以提高JAK3 mRNA的稳定性。JAK3表达升高激活JAK3/STAT3信号通路，而磷酸化的STAT3随后上调癌基因（如MYC）以及唾液酸转移酶ST6GALNAC5——后者直接增加细胞膜唾液酸化，而这是已知的免疫逃逸驱动因素。
Dysregulated expression of long non-coding RNAs (lncRNAs) has been shown to play a critical role in the tumorigenicity of clear cell renal cell carcinoma (ccRCC). Meanwhile, sialylation plays a pivotal role in cancer progression and in modulating the tumor immune microenvironment. However, how sialylation-immune-related lncRNAs (SIRLs) influence tumor immune microenvironment and progression of ccRCC remains unclear.
Using comprehensive cancer datasets, we identified key lncRNAs linked to both sialylation and immune modulation, constructing a prognostic risk model centered on the hub gene LINC01605 .
Patients classified as high-risk showed significantly poor survival outcomes and poor response to anti-PD-1 immunotherapy compared to low-risk individuals. Functional studies established LINC01605 's role in enhancing tumor aggressiveness and CD8 + T cell exhaustion. Knockdown of LINC01605 reduces total sialic acid levels in ccRCC cell membranes. Mechanistically, LINC01605 recruits IGF2BP2 to increase the stability of JAK3 mRNA. Elevated JAK3 expression activates JAK3/STAT3 signaling, and phosphorylated STAT3 subsequently upregulates oncogenes (e.g., MYC) as well as sialyltransferase ST6GALNAC5-which directly increases cell membrane sialylation, a known driver of immune evasion.
Our findings reveal the role of sialylation-immune-related lncRNAs in the immunosuppressive tumor microenvironment and cancer progression in ccRCC, providing a new framework for predicting patient outcomes and therapeutic responses.
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