<scp>STAT2</scp> Mediated Epigenetic and Epitranscriptomic Regulation of <scp>CD4</scp> ⁺ T Helper Cell Differentiation in Non‐Small Cell Lung Cancer ( <scp>NSCLC</scp> )

Non-small cell lung cancer (NSCLC) is an aggressive malignancy necessitating innovative therapeutic approaches to augment antitumour immunity. Our study examined the function of the STAT2 protein in CD4⁺ T helper cells, which are essential for the immune response to cancer. We utilised CRISPR/Cas9 to ablate STAT2 in CD4⁺ T cells from stage I NSCLC patients (n = 30), assessing its impact on cellular function and diverse epigenetic pathways. Our findings indicate that the depletion of STAT2 markedly enhances the anti-cancer efficacy of T lymphocytes. Deletion of STAT2 diminished oxidative stress, enhanced the synthesis of advantageous TH1 cytokines. STAT2 depletion reduced DNA methylation and R-loop formation. T cells deficient in STAT2 showed enhanced efficacy in activating cytotoxic T lymphocytes to eliminate cancer cells. These findings identify STAT2 as a crucial regulator of immune function in the lung cancer microenvironment. Targeted STAT2 inhibition in tumour-reactive T cells may reinstate anti-tumour immunity, although systemic inhibition requires further research on targeted intervention strategies.