[Novel clinical insights and frontier issues in alpha- fetoprotein-producing gastric cancer]

Alpha-fetoprotein-producing gastric cancer (AFPGC) represents a distinct clinical entity within the landscape of gastric malignancies, characterized by its aggressive biological behavior and unique clinicopathological profile. Most cases are classified under the chromosomal instability (CIN) subtype, featuring a molecular signature often marked by TP53 and MUC16 mutations, as well as significant amplifications of genes like ERBB2 and the cell cycle regulator CCNE1. As a serum tumor marker, alpha-fetoprotein (AFP) is typically highly elevated in AFPGC and correlates closely with tumor T-stage and patient prognosis. However, discordant expression is observed in some cases, characterized by positive intra-tumoral AFP expression in the presence of normal serum AFP levels. Moreover, intra-tumoral AFP plays an important role in both tumor invasiveness and immune evasion. It may promote tumor pro-liferation and metastasis by modulating immune cell activity. The high malignant potential of AFPGC may be attributable to its capacity to actively remodel the tumor milieu toward an immunosuppressive phenotype. Clinical studies have shown that the co-elevation of AFP with other markers, such as carcinoembryonic antigen (CEA), human chorionic gonadotropin (HCG), and protein induced by vitamin K absence or antagonist-Ⅱ (PIVKA-Ⅱ) often indicates a high malignant potential and a poor prognosis in gastric cancer, particularly in patients with advanced disease. Such concurrent detection of two or more biomar-kers facilitates the assessment of tumor aggressiveness as well as provides a clinical basis for early diagnosis and prognostic evaluation. Currently, there are no standardized guidelines for AFPGC treatment, and strategies often rely on individual pathological profile, tumor staging, and biomarker levels. In addition, immune checkpoint inhibitors (ICIs) have shown preliminary efficacy in some cases. Immunotherapy has demonstrated potential in AFPGC treatment, but the overall therapeutic outcomes and underlying mechanisms of resistance warrant further clinical validation and investigation. Individualized and multimodal therapeutic approaches are fundamental to improving clinical outcomes due to the high degree of heterogeneity in AFPGC. Therefore, a comprehensive evaluation of serum AFP levels, radiological findings, and pathological characteristics is essential for the development of personalized treatment regimens.