Its scope includes observational human studies, cell and animal experiments, and early-phase trials, while its key limitation is the heterogeneous and often preliminary nature of the available data. Heat shock proteins are highly conserved molecular chaperones that maintain cellular proteostasis. They assist newly synthesized polypeptides with folding, help refold damaged proteins, prevent aggregation and direct irreversibly damaged molecules toward degradation.

ATP-dependent families such as HSP70 and HSP90 support these processes, whereas small heat shock proteins operate as ATP-independent holdases that bind unfolded or partially folded proteins. The same stress-response machinery can give malignant cells a substantial survival advantage. In gastric cancer, elevated HSP70 has been associated with the anti-apoptotic protein Bcl-2 and reduced activity of Bax and caspase-3 in cells exposed to cisplatin or 5-fluorouracil.

HSP90 interacts with the selective-autophagy receptor NBR1, helping gastric cancer cells tolerate nutrient deprivation and hypoxia within the tumor microenvironment. The expression of these chaperones varies substantially among gastric cancers. Patient-derived organoid analysis cited by the review found marked differences in heat shock protein expression among organoids derived from different anatomical sites, with those differences linked to cytotoxic T-cell activity.

Higher HSP70 expression has been reported in poorly differentiated, highly invasive gastric tumors and in lymphovascular invasion. A systematic review and meta-analysis found associations between high HSP70 expression, tumor differentiation, intestinal-type gastric cancer and lymphovascular invasion, although it did not find a statistically significant relationship with overall survival. The evidence consequently supports HSP70 as a possible indicator of tumor phenotype and a mechanistic contributor to resistance, but not as an established stand-alone prognostic test.

Circulating HSP90α was elevated in patients with gastric cancer in the studies summarized by the review and correlated with tumor markers including CEA, CA125, CA153 and CA19-9. Its concentration was also associated with metastatic stage and with measures of T cells, B cells and the helper-to-suppressor T-cell ratio. When used alone, plasma HSP90 had diagnostic sensitivity of approximately 65%, limiting its performance as a stand-alone marker.

Combining plasma HSP90 with immune-cell parameters increased diagnostic specificity to 82% in the analysis reviewed and performed better than a CEA/CA19-9 panel. These results remain subject to validation in larger multicenter cohorts and across gastric cancer subtypes, and the review does not establish that such combinations are ready for routine clinical use. HSP27 has been linked to more advanced tumor stage and poorer outcome.

Its tissue concentration in gastric cancer was reported to be two to three times that in normal tissue, while high expression was associated with a 37% increase in recurrence risk. Mechanistic experiments indicate that HSP27 can inhibit PANoptosis, a coordinated form of programmed cell death, and contribute to an immunosuppressive environment through increased regulatory T-cell infiltration. It can also stimulate secretion of immunosuppressive cytokines including IL-10 and TNF-α, interfere with monocyte differentiation into mature dendritic cells and favor tumor-associated macrophage formation.

These findings connect HSP27 with both tumor-cell survival and the immune conditions that may protect gastric tumors from therapy, although the mechanisms are derived largely from experimental systems rather than clinical intervention studies. The tumor microenvironment reveals another complication because heat shock proteins can either reinforce or undermine antitumor immunity. HSP70-containing exosomes released by tumor cells can act as damage-associated molecular patterns, activate dendritic cells and strengthen antitumor responses.

In contrast, abundant intracellular or extracellular heat shock proteins can promote regulatory T cells and M2-like macrophages, suppress effector immune cells and alter angiogenic signaling. HSP70 interaction with TGF-β is associated with angiogenesis and suppression of antitumor immunity, while HSP90α can inhibit CD8-positive T-cell activity. HSF1, the principal transcriptional regulator of the heat shock response, is also active in gastric cancer-associated fibroblasts, where it regulates INHBA and THBS2 and affects extracellular-vesicle cargo, contributing to a more invasive tumor phenotype.

The apparently opposing immune effects make tumor stage, cell type and molecular subtype essential to any interpretation. At the signaling level, HSP90 stabilizes client proteins including c-MYC and c-MET, while HSP70 is associated with AKT-related survival signaling. HSP90 can bind LRP5 and prevent its ubiquitin-mediated degradation, activating AKT and Wnt/β-catenin signaling linked to epithelial–mesenchymal transition.

HSP90 can also form a complex with alpha-fetoprotein, while the lncRNA ZNRD1-AS1 can regulate the miR-9-5p/HSP90AA1 axis in connection with proliferation and metastasis. The regulatory effects are stage dependent: HSP70 binding to Smad3 can inhibit early TGF-β-induced epithelial–mesenchymal transition, whereas stabilization of TGF-β receptors by HSP90 can promote late-stage migration and metastasis. Reactive oxygen species can activate JNK signaling and raise HSP70 and HSP90, which then restrain excessive JNK activity and form a survival-promoting negative-feedback loop.

Drug development has focused most heavily on HSP90. Ganetespib and 17-AAG have entered or completed clinical testing, although the clinical record in gastrointestinal cancer is limited. In the review, a phase II study of ganetespib in advanced esophagogastric cancer enrolled 28 patients, with 26 evaluable for response.

The objective response rate was 4%, representing one response, median overall survival was 83 days, and the trial was terminated early for insufficient efficacy. Diarrhea affected 77% of participants and fatigue affected 65%. By contrast, a phase I study of the HSP70-directed agent Minnelide combined with paclitaxel enrolled 23 patients with refractory metastatic gastric cancer, most of whom had received at least three prior lines of treatment.

Among 11 evaluable patients, one had a partial response and five had stable disease, including two with stable disease longer than six months. These small, exploratory results do not establish clinical benefit. Combination strategies are being investigated to improve target coverage and counteract resistance.

Preclinical studies have paired HSP70 or HSP90 inhibitors with cisplatin, 5-fluorouracil, immune checkpoint inhibitors, photothermal therapy or photodynamic therapy. Nanocarrier systems have been designed to respond to acidic, enzyme-rich tumor environments or to combine heat treatment with HSP inhibition, with experimental reports of increased tumor targeting and reduced normal-tissue exposure. Dual inhibition of HSP70 and HSF1 has also been proposed as a way to block compensatory survival responses.

Clinical evaluation of pimitespib with nivolumab has begun, including a phase Ib program involving eight patients with gastric cancer among 44 participants with solid tumors. The limited sizes, varied disease populations and absence of randomized comparisons make it difficult to determine whether any combination produces durable benefit specifically in gastric cancer. Several obstacles explain why strong laboratory findings have not translated into established care.

First-generation inhibitors can have narrow therapeutic windows, including dose-limiting liver and gastrointestinal toxicity. Many also penetrate large, poorly vascularized tumors unevenly, leaving deeply seated regions incompletely exposed. More importantly, blocking HSP90 can activate HSF1, which increases compensatory proteins including HSP70, HSP40 and HSP27.

These alternative chaperones may preserve tumor survival when the primary target is inhibited, helping explain why single-agent HSP90 inhibition has been difficult to translate into sustained clinical benefit. The review identifies patient selection, isoform-selective drug design, improved delivery, rational combinations and reliable biomarkers as priorities for future research, but does not provide evidence that any proposed combination has yet become an established gastric cancer therapy.

Subject of Research: Heat shock protein biology, biomarker potential and targeted-therapy research in gastric cancer

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

Article References: Yanan, W., Jinpeng, Z., Peng, Z., Yuan, W., Qingyi, W., & Guoying, L. (2026). Progress in the Mechanism of Heat Shock Proteins in Gastric Cancer: From Biomarkers to Therapeutic Targets. Immunity, Inflammation and Disease, 14(10), Article e70542. https://doi.org/10.1002/iid3.70542

Image Credits: AI Generated

DOI: 10.1002/iid3.70542

Keywords: gastric cancer, heat shock proteins, HSP70, HSP90, HSP27, cancer biomarkers, tumor microenvironment, drug resistance, targeted therapy, clinical trials, HSF1, narrative review