Work

SerRS2 Identifies an Inflamed-Exhausted Hepatocellular Carcinoma Phenotype with Enhanced DNA-Sensing and Increased Anti-PD-1 Responsiveness

Year: 2026

Type: article

Abstract: Background: Seryl-tRNA synthetase 2 (SerRS2, encoded by SARS2 ) is a mitochondrial aminoacyl-tRNA synthetase essential for mitochondrial protein translation and homeostasis. Its clinical and immunological significance in hepatocellular carcinoma (HCC) remains unclear. Methods: Transcriptomic and clinical data from 371 TCGA-LIHC patients were analyzed to evaluate SerRS2 expression, prognosis, immune infiltration, T-cell exhaustion, and DNA-sensing-related features. Four single-cell RNA-sequencing datasets were analyzed to characterize the cellular distribution of SerRS2. Public immunotherapy cohorts were evaluated for associations between SerRS2 expression and immune checkpoint blockade outcomes, and an independent HCC cohort was used for qPCR validation. Group comparisons were performed using Student’s t -test or Wilcoxon rank-sum test, correlations using Pearson or Spearman analyses, and survival outcomes using Kaplan–Meier analysis with the Log rank test, as appropriate. Results: SerRS2 was significantly upregulated in HCC and associated with advanced pathological stage and poorer survival. Elevated SerRS2 expression was consistently associated with increased CD8+ T-cell infiltration and exhausted T-cell abundance and positively correlated with PDCD1, TOX, LAG3, HAVCR2 , and CTLA4 . SerRS2 was also positively associated with cGAS ( MB21D1 ) and DDX41 , but not STING1 , and SerRS2-high tumors exhibited increased exhaustion and DNA-sensing scores. Collectively, these findings support a SerRS2-associated inflamed-exhausted immune phenotype characterized by increased CD8+ T-cell infiltration, T-cell exhaustion-related features, and enrichment of DNA-sensing-related transcriptional programs. Single-cell analyses revealed heterogeneous SerRS2 expression across multiple cellular compartments, supporting its interpretation as a tissue-level rather than tumor-cell-specific signal. In public cross-tumor immunotherapy cohorts, elevated SerRS2 expression was associated with improved outcomes following PD-1 blockade, whereas comparable associations were not consistently observed for PD-L1 or CTLA-4 blockade, suggesting potential relevance of the SerRS2-associated immune phenotype to PD-1 blockade. These immune associations were further supported by qPCR validation in an independent HCC cohort. Conclusion: SerRS2 is associated with an inflamed-exhausted immune phenotype in HCC and may represent a candidate tissue-level biomarker for immune stratification. Its potential relevance to PD-1 blockade warrants prospective validation in HCC-specific immunotherapy cohorts. Keywords: SerRS2, hepatocellular carcinoma, immunotherapy, PD-1, T-cell exhaustion, DNA sensing, tumor immune microenvironment

Source: Journal of Inflammation Research

DOI: 10.2147/jir.s634229