Epigenetic Suppression of Histone Deacetylase 4 Boosts T Cell Homing via CXCR3 in Lung Cancer: A Step Toward Ultrasound-Guided Immunotherapy.

Lung cancer is the biggest reason of cancer-correlated death worldwide, owing primarily to immune evasion and poor response to current immunotherapies. The aim of this work was focused on the immunomodulatory effect of histone deacetylase 4 (HDAC4) in tumor immunological milieu, specifically CD8 T cell trafficking. Quantitative RT-PCR, immunofluorescence labeling, and FISH tests were used to determine HDAC4 and CXCR3 expression and location in lung cancer tissues. Flow cytometry assessed CD8 T cell function, and histological analysis revealed tumor development. Our results showed that HDAC4 was highly overexpressed in lung tumor samples, and it was associated with advanced clinical stage, lymph node metastases, and a worse overall survival rate. HDAC4 decreased CXCR3 expression, affecting CD8 T cell infiltration and effector function. HDAC4 knockdown increased CD8 T cell cytotoxicity, whereas CXCR3 inhibition reversed this effect. HDAC4 expression predicted poor survival with a ROC AUC of 0.78. SB939 treatment raised CXCR3 expression by 2.4 times and CD8 infiltration by 39%. These findings point to HDAC4 as a crucial epigenetic regulator of immune cell trafficking in lung cancer. Given the growing interest in ultrasound-assisted medication delivery and immunological priming, our findings point to HDAC4 as a viable therapeutic target in ultrasound-guided immunomodulatory methods for lung cancer.