Therapy-educated fibroblast states link treatment pressure to residual disease and acquired resistance in gastric cancer.

Chemotherapy, immune checkpoint blockade, HER2-targeted therapy, and anti-angiogenic therapy have widened treatment options for gastric cancer, yet residual disease and acquired resistance remain common. Cancer-associated fibroblasts (CAFs) are often classified as fixed subtypes, even though treatment exposes them to tissue injury, inflammatory cytokines, hypoxia, altered interstitial pressure, and matrix stress. We use treatment-shaped fibroblast state to describe a functional program that arises through reprogramming within resident fibroblasts, recruitment from a local mesenchymal source, or enrichment of a pre-existing state that survives therapy. An unpaired change in abundance cannot distinguish these mechanisms. The review follows four time points: the baseline ecosystem, acute therapeutic stress, the residual disease niche, and the acquired resistance circuit. Interferon-responsive and senescence-associated programs may be short-lived and either recruit or suppress immune cells. By contrast, persistent matrix, vascular, metabolic, and paracrine programs can protect residual tumor cells during treatment. Gastric cancer studies implicate TGF-β-SMAD, IL-6-JAK-STAT3, GAS6-AXL, CXCL12-CXCR4, NRP2, LOX, FAK, and extracellular matrix pathways. Longitudinal human evidence is limited and is sensitive to biopsy timing, spatial sampling, and single-cell dissociation bias. Translational studies should pair spatial specimens with collagen-turnover and extracellular-vesicle biomarkers, mechanically matched organoid-CAF co-cultures, and immunocompetent or humanized models. Treatment should disrupt or reprogram the state that sustains residual disease without removing fibroblast functions that support immunity or restrain tissue injury.