Abstract Gastric cancer remains a major clinical challenge worldwide with limited effective treatment options for advanced stages. APG-2449, an innovative multi-kinase inhibitor targeting FAK, ALK and ROS1, has demonstrated promising clinical potential in various malignancies, though its precise mechanism of action in gastric cancer requires further elucidation. This study aims to investigate the novel hypothesis that APG-2449 exerts its anti-tumor effects through inducing ferroptosis and subsequently activating anti-tumor immunity.Through comprehensive experimental approaches combining in vitro cell culture models and in vivo syngeneic mouse systems, we employed advanced techniques including Western blotting, chromatin immunoprecipitation, lipid peroxidation measurement, and multidimensional immune profiling.Our results demonstrate that APG-2449 effectively suppresses the FAK-AKT signaling pathway, resulting in FOXO1 dephosphorylation and nuclear translocation. Crucially, we provide direct evidence that FOXO1 binds to the ACSL4 promoter region, upregulating its transcription and subsequently driving lipid peroxidation that culminates in ferroptosis execution. Moreover, we establish that APG-2449-induced ferroptosis exhibits distinct immunogenic characteristics, triggering damage-associated molecular pattern release that promotes dendritic cell maturation and enhances CD8+ T cell infiltration and cytotoxic function within the tumor microenvironment. The therapeutic combination of APG-2449 with anti-PD-1 antibody generates significantly superior anti-tumor efficacy compared to either treatment alone.These findings illuminate a previously unrecognized dual mechanism of APG-2449 action: direct induction of ferroptosis via the FAK-AKT-FOXO1-ACSL4 axis coupled with potent activation of anti-tumor immunity, thereby providing a compelling rationale for clinical development of FAK inhibitor and immunotherapy combinations in gastric cancer management. Citation Format: Lin Zhang, Jing Xiao, Liqun Chen, Siyi Mao, Peiyao Song, Liqiong Yang, Runduan Lin, Miaozhen Qiu, Dajun Yang. FAK inhibitor APG-2449 triggers immunogenic ferroptosis in gastric cancer via the AKT-FOXO1-ACSL4 axis abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 5883.
Zhang et al. (Fri,) studied this question.