Results
HSPs exhibit heterogeneous expression in gastric cancer tissues, which is associated with tumor differentiation, lymph node metastasis, and progression. HSP70 expression correlates with poor differentiation, high invasiveness, intestinal-type gastric cancer, and lymphovascular invasion, and is involved in proliferation, migration, anti-apoptosis, and chemoresistance; inhibition of HSP70 enhances therapeutic sensitivity. HSP90ab1 interacts with LRP5, inhibits its ubiquitin-mediated degradation, activates AKT and Wnt/β-catenin signaling, and promotes epithelial-mesenchymal transition and invasive metastasis. Plasma HSP90α is elevated in gastric cancer patients and correlates with CEA, CA125, CA153, CA199, and immune cells, as well as with metastatic stage. HSP27 is elevated in gastric cancer tissues, promotes tumor growth by inhibiting PANoptosis, and is associated with progression and poor prognosis. HSPs also participate in TME remodeling by regulating cancer-associated fibroblasts, immune cells, vascular endothelial cells, and the extracellular matrix. They can both activate anti-tumor immunity and promote immunosuppression and immune evasion, and are involved in multidrug resistance. Mechanistically, HSPs interact with pathways such as PI3K/Akt, MAPK, and TGF-β, showing context-dependent and biphasic regulatory roles. HSP inhibitors, especially HSP90 inhibitors such as ganetespib, have shown preclinical and clinical activity in gastric cancer, but single-agent efficacy is limited by toxicity, poor tumor penetration, and HSF1-driven compensatory upregulation of HSP70, HSP40, and HSP27. Combination with chemotherapy, immunotherapy, photothermal/photodynamic therapy, and nanocarrier-based delivery has shown potential to improve efficacy. Dual targeting of HSP70/HSF1 and individualized combination regimens are proposed future directions.
