Abstract 516: SOX4 dictates gastric cancer progression by modulating the tumor immune microenvironment

Abstract SOX4 upregulation is common in multiple tumors, yet its role in shaping the immune microenvironment of gastric adenocarcinoma (GAC) remains unclear. This study investigates the influence of SOX4 on GAC progression and immune modulation. Using single-cell RNA sequencing, patient-derived models, and functional analyses, we examined SOX4 expression and its target genes in GAC. SOX4 was found to be highly expressed in both primary and metastatic GAC tissues, correlating with poor prognosis. Knockdown of SOX4 in GAC cells reduced tumor growth, migration, and colony formation and suppressed metastasis. Furthermore, SOX4 depletion enhanced T-cell cytokine production and promoted M2-macrophage repolarization in cocultures with patient-derived PBMCs and U937 cells. Conversely, SOX4 overexpression reinforced these aggressive phenotypes. RNA-seq analysis of SOX4 wildtype and knockout cells led to the identification of six drugs that could mimic the effects of SOX4 deletion, with Cucurbitacin-I and Tunicamycin emerging as potent inhibitors of GAC cell growth in patient-derived models. These findings highlight SOX4's role in driving GAC progression and immune evasion, offering potential therapeutic avenues for targeting SOX4 in GAC treatment. Citation Format: Gengyi Zou, Katsuhiro Yoshimura, Yibo Fan, Ruiping Wang, Kohei Yamashita, Shan Shao, Ailing Scott, Jiankang Jin, Melissa P. Pizzi, Matheus Silva, Xiaodan Yao, Calena Brown, Rebecca Waters, Shumei Song, Linghua Wang, Shilpa Dhar, Jaffer A. Ajani. SOX4 dictates gastric cancer progression by modulating the tumor immune microenvironment [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 516.