DNAJA1 as a Modulator of CD8+ T-Cell Function and Prognosis in Lung Cancer: Implications for Immune Regulation and Therapeutic Targeting.

Abstract

In lung adenocarcinoma (LUAD), dysfunctional CD8⁺ T-cells and an immunosuppressive tumour microenvironment (TME) are major barriers to effective immunotherapy, yet the molecular regulators coordinating T cell exhaustion and macrophage polarization remain undefined. To address this, we integrated single-cell RNA sequencing, TCGA transcriptome and methylation data, co-culture assays, chromatin profiling, functional assays, and xenograft models to investigate the role of DNAJA1 in immune regulation and tumor progression. Our results demonstrated that DNAJA1 was upregulated in exhausted CD8⁺ T-cells in lung cancer tissues and correlated positively with exhaustion markers including PD-1, TIM-3, and LAG-3. Notably, exhausted CD8⁺ T-cells exhibited DNAJA1 promoter hypomethylation and enrichment of activating histone modifications H3K4me3 and H3K27ac, while inhibiting the activation of H3K4me3 and H3K27ac reduced DNAJA1 expression. Additionally, DNAJA1 overexpression upregulated M2-associated genes (CD206 and IL-10), while its knockdown enhanced the expression of M1-associated genes (CD86 and IL-12). Furthermore, DNAJA1 promoted tumour cell proliferation, and its expression level showed a moderate positive correlation with PD-L1. Collectively, these findings establish DNAJA1 as an epigenetically activated regulator that drives CD8⁺ T-cell exhaustion and protumor macrophage polarization, highlighting its dual role as a functional immunomodulator and potential biomarker for stratifying LUAD patients with immune-dysregulated TME.