Pan-cancer analysis reveals HDAC1 as a key regulator of immune infiltration and T cell exhaustion

Abstract Histone deacetylases (HDACs) are critical epigenetic regulators that play pivotal roles in tumorigenesis and cancer progression. Class I HDACs have garnered significant attention due to their essential functions in cell proliferation and differentiation; however, their baseline expression patterns within the immune system and specific mechanisms of action in the tumor microenvironment (TME) remain incompletely understood. This study systematically analyzed the expression profiles of Class I HDAC family members in immune tissues and comprehensively investigated their expression levels, prognostic significance, and associations with tumor immune infiltration and T cell exhaustion across multiple cancer types. HDAC1 emerged as the most abundant Class I HDAC member in major murine immune organs, with expression levels significantly surpassing HDAC2 and HDAC3 in spleen, thymus, lymph nodes, and bone marrow tissues. Pan-cancer analysis using TCGA datasets revealed that HDAC1 is universally upregulated in the majority of tumor types and that its elevated expression correlates significantly with poor patient prognosis. Mechanistic analysis demonstrated that HDAC1 expression levels negatively correlate with tumor immune infiltration, suggesting its potential role in suppressing anti-tumor immune responses. Importantly, we discovered that HDAC1 expression positively correlates with multiple key T cell exhaustion markers, including PD-1, CTLA4, LAG3, and TIM3, revealing its potential involvement in T cell dysfunction. This study provides the first systematic evidence that HDAC1 represents the predominant Class I HDAC member in immune system expression. Its aberrant overexpression across cancers serves not only as an important predictor of poor prognosis but also closely associates with suppressed tumor immune infiltration and T cell exhaustion. These findings elucidate the critical role of HDAC1 in tumor immune evasion and provide strong rationale for its development as both a novel therapeutic target and prognostic biomarker for cancer immunotherapy.