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

Published in

International journal of molecular medicine. Volume 58. Issue 3. Epub Jul 10, 2026.

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.

PMID:
42429070
Bibliographic data and abstract were imported from PubMed on 10 Jul 2026.

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