Background: Gastric cancer (GC) has a poor response to current chemo-immunotherapy. Ferroptosis is a newly recognised form of iron-dependent cell death that can enhance drug efficacy; however, the key regulator factors and mechanisms governing ferroptosis in gastric cancer remain unclear. This study aimed to investigate the synergistic antitumor effect of oxaliplatin combined with a programmed death-1 (PD-1) inhibitor in gastric cancer and elucidate the regulatory role of six-transmembrane epithelial antigen of prostate 4 (STEAP4) in ferroptosis. Methods: Subcutaneous mouse forestomach carcinoma (MFC) gastric cancer xenograft models were successfully developed using immunodeficient BALB/c nude mice and randomized into control, oxaliplatin, PD-1 inhibitor, and combination groups for in vivo efficacy assessment. In vitro, STEAP4 was silenced in MFC cells via siRNA to evaluate its impact on drug sensitivity. Western blotting, qRT-PCR (Quantitative Reverse Transcription Polymerase Chain Reaction), transmission electron microscopy, and biochemical assays were used to detect STEAP4 expression and ferroptosis-related markers. Results: The combination treatment significantly suppressed tumor growth compared with monotherapies (p 2+ and ROS (Reactive Oxygen Species) levels, upregulation of ACSL4, and downregulation of glutathione peroxidase 4 (GPX4) and SLC7A11. STEAP4 expression was markedly elevated in tumor tissues after combination therapy (p STEAP4 knockdown reduced the sensitivity of MFC cells to the combination and reversed ferroptosis induction by suppressing ACSL4 and restoring GPX4 and SLC7A11 expression. Conclusion: The combination of oxaliplatin and a PD-1 inhibitor exerts potent synergistic effects in gastric cancer through STEAP4 upregulation, which promotes ferroptosis and enhances treatment sensitivity. STEAP4 may serve as a potential biomarker and therapeutic target for optimizing combination therapy in gastric cancer.
Zou et al. (Thu,) studied this question.
Synapse has enriched 5 closely related papers on similar clinical questions. Consider them for comparative context: