Stress-specific 14-3-3-client modules in digestive cancers: an evidence-graded review of adaptive survival and therapy resistance.

14-3-3 proteins are phosphoserine- and phosphothreonine-binding adaptors that regulate client localization, stability and activity under cellular stress. This narrative review synthesizes stress-specific 14-3-3-client modules in gastric, colorectal, pancreatic, hepatocellular and biliary cancers. Modules were classified as high, moderate, early/context-dependent or background according to mechanistic evidence, functional perturbation, client mapping, treatment-state validation and clinical association. In gastric cancer, G3BP stress granule assembly factor 1 (G3BP1) cooperates with YWHAZ-encoded 14-3-3ζ to retain pro-apoptotic Bax in the cytoplasm. In colorectal cancer, SFN-encoded 14-3-3σ restricts Yin Yang 1 (YY1), sustaining the unfolded protein response and chemotherapy tolerance. In pancreatic cancer, SFN-encoded 14-3-3σ interacts with Yes-associated protein 1 (YAP1) to promote ribonucleotide reductase expression and gemcitabine resistance. In hepatobiliary cancers, SFN-related modules support anoikis resistance but remain context dependent. Clinically relevant units are stress-specific 14-3-3-client complexes rather than total 14-3-3 expression.