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GRP78 dysregulation: A proposed molecular mechanism linking the tumor microenvironment to sepsis susceptibility in patients with cancer (Review)

  • Authors:
    • Hang Ruan
    • Meipeng Zhu
    • Shi-Yan Liu
    • Li-Juan Zou
    • Shu-Sheng Li
  • View Affiliations / Copyright

    Affiliations: Department of Critical‑care Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, P.R. China, Department of Pediatric Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, P.R. China, Department of Rehabilitation, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, P.R. China
    Copyright: © Ruan et al. This is an open access article distributed under the terms of Creative Commons Attribution License.
  • Article Number: 248
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    Published online on: July 7, 2026
       https://doi.org/10.3892/ijmm.2026.5919
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Abstract

Patients with cancer are at a significantly higher risk of sepsis, which is associated with substantially increased morbidity and mortality. However, the intrinsic molecular mechanisms driving sepsis susceptibility in this high‑risk population remain unclear. Glucose‑regulated protein 78 (GRP78), the master regulator of endoplasmic reticulum stress, is aberrantly overexpressed and is involved in cell membrane translocation and extracellular release driven by the tumor microenvironment and anticancer therapies. To date, no clinical cohort study has directly established a causal link between GRP78 dysregulation and sepsis incidence or mortality in patients with cancer. The present narrative review therefore relied predominantly on indirect evidence from in vitro studies, animal models and non‑oncologic sepsis cohorts. Despite these limitations, the present study advanced the hypothesis that GRP78 dysregulation may increase sepsis susceptibility through two convergent mechanisms: i) Facilitating pathogen invasion via cell‑surface GRP78, which serves as a critical coreceptor for specific viruses and Mucorales fungi and ii) orchestrating immunosuppression through secreted GRP78‑mediated dampening of innate immune responses. Direct evidence for the function of cell‑surface GRP78 as a bacterial adhesion receptor is limited; its contribution to bacterial sepsis, the predominant clinical form, is primarily indirect and mediated by host inflammatory dysregulation, phagocytic impairment and barrier disruption. The present review provided a preliminary theoretical framework for future investigations into GRP78‑mediated sepsis susceptibility in patients with cancer, with hypothetical implications for risk stratification and targeted interventions, pending dedicated clinical validation in oncology‑specific cohorts.
View Figures

Figure 1

GRP78 dysregulation connects the
tumor microenvironment and sepsis susceptibility. Tumor-derived
GRP78 drives sepsis pathogenesis through dual mechanisms. i)
Pathogen invasion: csGRP78 acts as a critical coreceptor,
facilitating the entry of specific viruses (such as SARS-CoV-2,
dengue virus and Japanese encephalitis virus) and Mucorales fungi
(such as Rhizopus spp.), thereby increasing infection
efficiency. For bacterial pathogens, the predominant cause of
clinical sepsis, direct evidence for csGRP78 as an adhesion or
invasion receptor is currently limited to Mycoplasma
hyopneumoniae (a nonhuman pathogen). In bacterial infections,
the predominant cause of clinical sepsis, csGRP78 does not function
as a canonical adhesion receptor for major human pathogens.
Instead, GRP78 contributes to the progression of bacterial sepsis
through the indirect regulation of host inflammatory responses,
phagocytic function and epithelial barrier integrity. ii)
Immunosuppression: sGRP78 functions as a potent immunosuppressive
cytokine, triggering a 'cytokine storm' in early sepsis followed by
profound immune paralysis in late sepsis. This immunosuppressive
milieu, combined with direct pathogen invasion, compromises host
defense mechanisms, leading to uncontrolled infection, vascular
leakage, multiorgan dysfunction and ultimately septic shock. The
figure was constructed using the Figdraw 2.0 tool (https://www.figdraw.com/#/), with official
authorization obtained by the authors (authorization no.
PPPIU1c449). GRP78, glucose-regulated protein 78; cs, cell-surface;
s, secreted.

Figure 2

Schematic of GRP78-mediated
maintenance of ER homeostasis and the UPR regulatory feedback loop
under physiological and stress conditions. GRP78 is expressed in
three well-characterized functional states: the ER-resident form
(ER-GRP78) with intrinsic protein-folding chaperone activity, the
cell surface-localized form (csGRP78) that acts as a transmembrane
signaling receptor and the soluble extracellular form (sGRP78) that
acts as a secreted intercellular signaling factor. Under resting
conditions, ER-resident GRP78 maintains cellular homeostasis
through three key functions: preserving ER proteostasis through its
molecular chaperone activity; indirectly inhibiting apoptosis
through the suppression of CHOP and caspase activation; and
negatively regulating the UPR by binding to and repressing three
core ER stress sensors (PERK, IRE1 and ATF6). Upon exposure to
pathological stress, unfolded/misfolded proteins that accumulate in
the ER compete for binding to GRP78, leading to the differential
activation of three interconnected UPR branches: The
PERK-eIF2α-ATF4, ATF6 cleavage-nuclear translocation and IRE1-sXBP1
pathways. The ATF6 and IRE1-XBP1 pathways primarily converge to
upregulate GRP78 transcription, whereas PERK signaling contributes
indirectly, resulting in the formation of a negative feedback loop
to restore ER homeostasis. The figure was constructed using the
Figdraw 2.0 tool (https://www.figdraw.com/#/), with official
authorization obtained by the authors (authorization no.
RPWUW59df5). GRP78, glucose-regulated protein 78; ER, endoplasmic
reticulum; ER-GRP78, endoplasmic reticulum-resident GRP78; csGRP78,
cell-surface GRP78; sGRP78, secreted GRP78; UPR, unfolded protein
response; PERK, protein kinase R-like ER kinase; IRE1,
inositol-requiring enzyme 1; ATF6, activating transcription factor
6; CHOP, C/EBP homologous protein; eIF2α, eukaryotic initiation
factor 2 alpha; ATF4, activating transcription factor 4; sXBP1,
spliced X-box binding protein 1; XBP1, X-box binding protein 1.
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Copy and paste a formatted citation
Spandidos Publications style
Ruan H, Zhu M, Liu S, Zou L and Li S: GRP78 dysregulation: A proposed molecular mechanism linking the tumor microenvironment to sepsis susceptibility in patients with cancer (Review). Int J Mol Med 58: 248, 2026.
APA
Ruan, H., Zhu, M., Liu, S., Zou, L., & Li, S. (2026). GRP78 dysregulation: A proposed molecular mechanism linking the tumor microenvironment to sepsis susceptibility in patients with cancer (Review). International Journal of Molecular Medicine, 58, 248. https://doi.org/10.3892/ijmm.2026.5919
MLA
Ruan, H., Zhu, M., Liu, S., Zou, L., Li, S."GRP78 dysregulation: A proposed molecular mechanism linking the tumor microenvironment to sepsis susceptibility in patients with cancer (Review)". International Journal of Molecular Medicine 58.3 (2026): 248.
Chicago
Ruan, H., Zhu, M., Liu, S., Zou, L., Li, S."GRP78 dysregulation: A proposed molecular mechanism linking the tumor microenvironment to sepsis susceptibility in patients with cancer (Review)". International Journal of Molecular Medicine 58, no. 3 (2026): 248. https://doi.org/10.3892/ijmm.2026.5919
Copy and paste a formatted citation
x
Spandidos Publications style
Ruan H, Zhu M, Liu S, Zou L and Li S: GRP78 dysregulation: A proposed molecular mechanism linking the tumor microenvironment to sepsis susceptibility in patients with cancer (Review). Int J Mol Med 58: 248, 2026.
APA
Ruan, H., Zhu, M., Liu, S., Zou, L., & Li, S. (2026). GRP78 dysregulation: A proposed molecular mechanism linking the tumor microenvironment to sepsis susceptibility in patients with cancer (Review). International Journal of Molecular Medicine, 58, 248. https://doi.org/10.3892/ijmm.2026.5919
MLA
Ruan, H., Zhu, M., Liu, S., Zou, L., Li, S."GRP78 dysregulation: A proposed molecular mechanism linking the tumor microenvironment to sepsis susceptibility in patients with cancer (Review)". International Journal of Molecular Medicine 58.3 (2026): 248.
Chicago
Ruan, H., Zhu, M., Liu, S., Zou, L., Li, S."GRP78 dysregulation: A proposed molecular mechanism linking the tumor microenvironment to sepsis susceptibility in patients with cancer (Review)". International Journal of Molecular Medicine 58, no. 3 (2026): 248. https://doi.org/10.3892/ijmm.2026.5919
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