Immunotherapy rechallenge in gastric cancer: resistance mechanisms, molecular stratification, and precision decision-making.

Background/objectives: Immune checkpoint inhibitors (ICIs) have changed the treatment landscape of advanced gastric cancer (GC). However, acquired resistance remains common. For patients who initially benefit and later progress, immunotherapy rechallenge is biologically plausible but still investigational. Approach: This narrative review synthesizes mechanistic, translational, biomarker, and clinical evidence on ICI resistance and rechallenge in GC. Results: Resistance may involve tumor-intrinsic plasticity, hypoxia- and metabolism-driven remodeling, impaired antigen presentation, suppressive tumor microenvironment (TME) components, T-cell exhaustion, and compensatory checkpoints such as Lymphocyte-activation gene 3 (LAG-3), T-cell immunoglobulin and mucin-domain containing-3 (TIM-3), T-cell immunoreceptor with Ig and ITIM domains(TIGIT), and V-domain Ig suppressor of T cell activation (VISTA). Epstein-Barr virus (EBV)-positive and Microsatellite instability-high (MSI-H)/Deficient mismatch repair (dMMR) tumors often show immune-inflamed features, but they may still develop HLA class I loss, immune editing, or cold-tumor phenotypes. Direct GC-specific rechallenge evidence remains limited and is mainly retrospective or case-series based. Therefore, mechanistic and non-GC data should be interpreted as indirect and hypothesis-generating. Conclusions: ICI rechallenge in GC should be regarded as a biomarker-informed investigational strategy rather than a standard of care. Prospective trials, standardized definitions, validated biomarkers, and careful toxicity monitoring are needed.