Progress in the Mechanism of Heat Shock Proteins in Gastric Cancer: From Biomarkers to Therapeutic Targets.

backgroundGastric cancer remains a major challenge in public health, with low early diagnosis rates and poor prognosis for advanced patients. Heat shock proteins (HSPs) are highly conserved molecular chaperones that maintain proteostasis and promote cell survival under stress. Aberrantly elevated HSPs in gastric cancer are closely linked to tumor initiation, invasion, metastasis, and poor prognosis. This review aims to comprehensively synthesize the latest advances concerning HSPs in gastric cancer across three core dimensions: their utility as diagnostic/prognostic biomarkers, their regulatory mechanisms in key signaling pathways and the tumor microenvironment (TME), and their viability as therapeutic targets. MATERIALS AND

methodsThis review is structured as a narrative synthesis of the literature. A structured search was performed across PubMed, EMBASE, Web of Science Core Collection, and Cochrane Library, from their inception to March 2026. The search strategy combined keywords and MeSH terms related to three domains: (1) HSPs; (2) gastric cancer; and (3) therapeutics/inhibitors. Two authors independently screened titles and abstracts, and disagreements were resolved through discussion or consultation with a third author. Observational human studies, experimental studies (in vitro and in vivo), and preclinical animal models relevant to the three thematic pillars were included. Reference lists of included papers and relevant review articles were also manually searched. Given the broad scope and qualitative, integrative nature of this review, no formal quantitative meta-analysis or standardized risk-of-bias assessment was performed. Instead, findings were synthesized thematically, emphasizing critical appraisal of conflicting data, identification of knowledge gaps, and discussion of translational barriers.

resultsHSPs 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. DISCUSSION: HSPs are key molecules in the initiation and progression of gastric cancer. Their abnormal expression reflects tumor biological characteristics and provides new avenues for clinical diagnosis and treatment. The mechanisms of HSPs in gastric cancer are complex, involving stress responses, protein folding/repair, signaling pathway regulation, and immune evasion, which determine their critical roles in the TME. As biomarkers, HSPs have shown sensitivity and specificity in early diagnosis and prognosis, but clinical translation still faces challenges such as inhibitor selection, protection of normal cells, and drug resistance. Future research requires multidisciplinary collaboration to resolve existing controversies, clarify molecular mechanisms, and develop efficient and safe targeted drugs, so as to improve the diagnosis and treatment outcomes of gastric cancer and enhance patient survival and quality of life.