<p>Immune checkpoint inhibitors (ICIs) have reshaped the treatment landscape for advanced cancers; however, a substantial proportion of patients fail to benefit from ICI therapy, and reliable predictive biomarkers remain limited. This study aimed to investigate the immunological relevance of helicase-like transcription factor (HLTF) and its potential therapeutic implications in hepatocellular carcinoma (HCC).</p><p>HLTF expression was elevated across multiple cancer types, with particularly high levels observed in HCC. Increased HLTF expression was significantly associated with advanced tumor stage, higher histological grade, TP53 mutations, and lymph node metastasis. Moreover, high HLTF expression correlated with poorer overall survival, disease-specific survival, and progression-free interval in patients with HCC, indicating its potential value as a prognostic biomarker. Consistent with data from the Human Protein Atlas, HLTF protein expression was 74.51% higher in HCC tissues than in adjacent non-tumor tissues, and a similar pattern was observed at the transcriptional level. Immune infiltration analysis revealed a negative association between HLTF expression and CD8⁺ T cell infiltration, despite notable HLTF enrichment within CD8⁺ T cells themselves. Clear differences in pDC/CD8⁺ T cells were observed between HLTF-high and HLTF-low subgroups, further supporting an inverse relationship between HLTF and CD8⁺ T cells in HCC TMA cohorts. In addition, we observed that tumor tissues from nonresponders displayed greater levels of HLTF compared to those from responders in our cohort.</p><p>Taken together, our study points out that HLTF acts as a critical marker that dwindles the effectiveness of ICIs in HCC sufferers. More trials with large numbers of patients are imperative to validate its application as a beneficial biomarker for ICIs.</p>