Sialylation-immune-related lncRNA LINC01605 promotes tumor-infiltrating CD8+ T cell exhaustion and malignancy of clear cell renal cell carcinoma

TL;DR

This study identifies a long non-coding RNA, LINC01605, that promotes tumor growth and immune evasion in kidney cancer by increasing sialylation and CD8+ T cell exhaustion.

Contribution

The study reveals a novel sialylation-immune-related lncRNA, LINC01605, that drives ccRCC progression and T cell exhaustion through JAK3/STAT3 signaling.

Findings

LINC01605 knockdown reduces sialic acid levels and tumor aggressiveness in ccRCC.

LINC01605 promotes JAK3/STAT3 signaling, leading to increased sialyltransferase ST6GALNAC5 expression.

High LINC01605 risk scores correlate with poor survival and anti-PD-1 immunotherapy response in ccRCC patients.

Abstract

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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