Signature Construction Associated with Tumor-Infiltrating Macrophages Identifies IRF8 as a Novel Biomarker for Immunotherapy in Advanced Gastric Cancer

Advanced gastric cancer (AGC) is characterized by poor prognosis and limited responsiveness to immunotherapy. Tumor-associated macrophages (TAMs) play a pivotal role in cancer progression and therapeutic outcomes. In this study, we developed a novel gene signature associated with M1-like TAMs using data from the Gene Expression Omnibus (GEO) and The Cancer Genome Atlas (TCGA) to predict prognosis and immunotherapy response. This gene signature was determined as an independent prognostic indicator for AGC, with high-risk patients exhibiting an immunosuppressive tumor immune microenvironment (TIME) and poorer survival outcomes. Furthermore, Interferon regulatory factor 8 (<i>IRF8</i>) was identified as a key gene and validated through in vitro and in vivo experiments. <i>IRF8</i> overexpression reshaped the suppressive TIME, leading to an increased presence of M1-like TAMs, IFN-γ⁺ CD8⁺ T cells, and Granzyme B⁺ CD8⁺ T cells. Notably, the combination of <i>IRF8</i> overexpression and anti-PD-1 therapy significantly inhibited tumor growth in syngeneic mouse models. AGC patients with elevated <i>IRF8</i> expression were found to be more responsive to anti-PD-1 treatment. These findings highlight potential biomarkers for prognostic evaluation and immunotherapy in AGC, offering insights that could guide personalized treatment strategies.