ER-GRP78 represents the canonical functional state of GRP78, which is predominantly localized within the ER lumen (16). Under physiological conditions, ER-GRP78 is maintained within the endoplasmic reticulum through the binding of its C-terminal KDEL (Lys-Asp-Glu-Leu) sequence to KDEL receptors (KDELRs) (17). As the central regulator of the UPR, ER-GRP78 binds to and inhibits transmembrane stress sensors, including protein kinase R-like ER kinase (PERK), inositol-requiring enzyme 1 alpha (IRE1α) and activating transcription factor 6 (ATF6), thereby maintaining these proteins in an inactive conformation (18,19). When unfolded or misfolded proteins accumulate within the ER lumen, GRP78 dissociates from these sensors to bind to the aberrant proteins, initiating the UPR signaling cascade. This response restores proteostasis through three coordinated mechanisms: Inhibition of global protein synthesis, upregulation of molecular chaperone expression and enhancement of ER-associated degradation. Under normal physiological conditions, the vast majority of GRP78 exists as ER-GRP78, serving as the cornerstone of cellular protein quality control.

GRP78 can be secreted extracellularly as sGRP78 and is detected in various body fluids, including blood, urine and cerebrospinal fluid (15). Its secretion occurs through both canonical (ER-Golgi apparatus pathway) and noncanonical (direct release via exosomes or vesicles) mechanisms (20). In the tumor microenvironment, exosomes secreted by GRP78-induced M2 macrophages can transfer GRP78 to colorectal cancer cells, promoting cancer stem cell properties and chemotherapeutic resistance (15,20). Clinical investigations revealed significantly elevated serum sGRP78 levels in lung patients with cancer, with 80.2% sensitivity and 68.9% specificity for an early-stage lung cancer diagnosis and an area under the curve of 0.788, outperforming the conventional biomarker carcinoembryonic antigen (14). sGRP78 levels are positively correlated with the tumor burden, disease stage and a poor prognosis; notably, non-small cell lung cancer (NSCLC) patients with high sGRP78 expression experience significantly shorter overall survival (14).

In response to tumor microenvironmental stressors (hypoxia, nutrient deprivation and therapeutic stress) or ER stress induction, GRP78 translocates to the cell surface to form csGRP78 through the following four primary mechanisms.

First, the ER retention and recycling system is saturated. Under pathological stress conditions, sustained GRP78 overexpression exceeds the retrograde transport capacity of KDEL receptors (KDELRs) (16). Consequently, substantial quantities of unretrieved GRP78 enter the anterograde secretory pathway via COPII-coated vesicles and are ultimately trafficked to the plasma membrane through post-Golgi secretory vesicles (21).

Second, KDELRs are dysfunctional. Pathological conditions induce the aberrant activation of the tyrosine-protein kinase SRC, which mediates the phosphorylation of ASAP1 and the accumulation of Arf1-GTP, leading to the dispersion of KDEL receptors from the Golgi complex (17,22). This process downregulates their retrograde transport activity, impairing the effective retrieval of escaped GRP78 and facilitating its entry into secretory pathways (22).

Third, vesicular trafficking and secretory pathway-mediated mechanisms are involved. GRP78 is trafficked through two routes: One subset follows the canonical secretory pathway and is transported from the ER to the Golgi apparatus via COPII vesicles and subsequently to the plasma membrane through secretory vesicles (22). A second subset utilizes exosome-mediated pathways, potentially bypassing Golgi apparatus processing through alternative routes (23).

Fourth, plasma membrane anchoring occurs. GRP78 is trafficked to the plasma membrane and stably anchored to the outer membrane leaflet through interactions with cell surface glycoproteins, phosphatidylserine and other lipid moieties, resulting in the formation of functional csGRP78 (23). Following membrane anchoring, csGRP78 undergoes specific conformational rearrangements that expose its substrate-binding domain to the extracellular milieu, significantly increasing ligand accessibility (24). This structural adaptation confers the capacity to specifically bind extracellular ligands, pathogen structural proteins and cell surface receptors (17).

Notably, the expression of csGRP78 is markedly increased on the surface of multiple solid tumor cells but is minimal on cells in normal tissues, establishing it as an ideal target for tumor-specific therapeutic interventions.

Tumorigenesis and progression are accompanied by persistent ER stress driven by malignant cell proliferation, hypoxia, nutrient deprivation and antitumor treatment, which are the core drivers of aberrant GRP78 overexpression, subcellular redistribution (especially membrane translocation) and extracellular release (6,25). Unlike total intracellular GRP78, which acts primarily as a chaperone to regulate tumor progression and therapeutic resistance, csGRP78 and sGRP78 represent plausible molecular mediators that may link tumor pathology to increased sepsis susceptibility in patients with cancer, but these findings require direct clinical validation.

Notably, most existing studies have focused on the correlations between GRP78 expression and the tumor stage, chemotherapy resistance and overall survival, while direct clinical evidence verifying the causal association between GRP78 dysregulation and sepsis incidence/prognosis in patients with cancer remains scarce. Table I systematically summarized the changes in GRP78 expression directly related to the infection/sepsis risk across common human malignancies, with a focus on membrane expression and secretion features that are closely associated with sepsis pathogenesis (15,26-61).

Chronic, persistent ER stress in the tumor microenvironment not only upregulates total GRP78 expression but also, more importantly, specifically increases its membrane translocation and extracellular release (6,8). These two processes represent the primary sources of persistently elevated csGRP78 and sGRP78 levels in patients with cancer, resulting in the formation of an immunosuppressive microenvironment that may contribute to systemic immune dysfunction (62,63). Compared with physiological GRP78 trafficking in normal cells, tumor cells and antitumor treatments increase GRP78 membrane translocation and secretion through multiple nonredundant mechanisms, including SRC-mediated KDELR dispersion and DNAJC3-dependent endosomal transport, with significant heterogeneity across tumor types and treatment modalities (17).

The most potent constitutive induction of GRP78 membrane translocation and secretion occurs in highly secretory tumors and tumors with sustained hypoxia/ER stress (26,53). Among these tumors, hematologic malignancies and highly hypoxic solid tumors show the most significant baseline GRP78 membrane localization and secretion (53,64). The core mechanisms include two aspects, which are described below.

Persistent inactivation of the ER retention-retrieval system: Oncogenic activation of SRC kinase in tumor cells disrupts KDEL receptor-mediated retrograde transport by inducing KDELR dispersion from the Golgi apparatus, while the ER stress-induced upregulation of GRP78 promotes its translocation to the cell surface via multiple mechanisms, including the suppression of Golgi-to-ER retrieval (65).

Hyperactivation of noncanonical secretory pathways: Under hypoxic and nutrient-deprived conditions, tumor cells widely utilize exosome-mediated unconventional secretion to release GRP78 into the extracellular space (66). This noncanonical pathway operates alongside classical secretion mechanisms, with ER-stressed tumor cells showing enhanced packaging of GRP78 into exosomes that bypass traditional ER-Golgi quality control checkpoints. This effect is most prominent in GBM, PDAC and other hypoxic solid tumors and is the main source of circulating GRP78 in patients with advanced malignancies (23,53).

Antitumor treatments are the most important exogenous inducers of GRP78 membrane translocation and extracellular release and are the core drivers of the sharp increase in the sepsis risk in patients with cancer during treatment. Among these treatments, myelosuppressive chemotherapy, multitarget tyrosine kinase inhibitors (TKIs) and androgen deprivation therapy (ADT) have the strongest induction effects.

Chemotherapy: Platinum-based chemotherapy and anthracycline-based chemotherapy significantly exacerbate ERS in tumor cells, upregulate GRP78 expression and simultaneously promote its membrane translocation and exosomal secretion (67,68). This process forms a vicious cycle of 'treatment-induced stress-GRP78 dysregulation-immunosuppression-infection susceptibility', which is the core mechanism of postchemotherapy sepsis in patients with hematologic malignancies and solid tumors. Paradoxically, while chemotherapy aims to eliminate tumor cells, it inadvertently amplifies GRP78-mediated immunosuppression, creating a transient 'window of vulnerability' where the host defense against pathogens is severely compromised.

Targeted therapy: Sorafenib activates the IRE1α-mediated unfolded protein response pathway, promoting GRP78 membrane translocation and extracellular release (53). The sGRP78 level measured in patients after targeted therapy can be higher than that at baseline, which is closely related to the increased infection risk during treatment (53). EGFR-TKIs may disrupt ER homeostasis and are associated with an increased infection risk (69).

Hormone therapy: ADT may upregulate GRP78 expression; however, direct clinical evidence linking ADT-induced GRP78 dysregulation to sepsis risk in prostate patients with cancer is currently lacking (55,56).

Accumulating evidence from in vitro and in vivo studies confirms that csGRP78 acts as a bona fide functional receptor or critical coreceptor for a broad spectrum of pathogenic viruses (73,74,79). It mediates viral invasion via two core mechanisms: Acting as a primary receptor to directly drive viral adhesion and endocytosis or as an attachment cofactor to increase viral binding affinity to cognate receptors and modulate post-invasion intracellular trafficking, thereby markedly increasing infection efficiency (74). This pro-infective role has been validated across multiple viral families (including Flaviviridae, Coronaviridae, Orthomyxoviridae and Enteroviridae), positioning GRP78 as a promising broad-spectrum antiviral target (21).

For Flaviviridae members, including dengue virus, Zika virus and Japanese encephalitis virus, GRP78 serves as a key host factor via direct interactions with viral envelope proteins and silencing/knockdown of GRP78 consistently inhibits viral invasion, replication and progeny production (75-80). csGRP78 also acts as a critical coreceptor for Coxsackievirus A9 (Enteroviridae), an essential host factor for influenza A virus (Orthomyxoviridae) and a key cooperative receptor for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2, Coronaviridae) (81-83). For SARS-CoV-2, in particular, GRP78 directly binds the spike protein receptor-binding domain and forms a functional complex with ACE2 to mediate viral entry, with clinical data linking elevated sGRP78 levels to COVID-19 infection susceptibility (21,73).

The receptor/coreceptor function of csGRP78 in driving viral infection has also been confirmed for retroviruses, filoviruses and other pathogenic viruses (84,86,89,99). Collectively, these findings establish csGRP78 as a core host factor that mediates viral invasion, which underpins the progression to severe disease and sepsis secondary to viral infection (Table III) (73-90,99-104).

csGRP78 serves as a critical receptor for host cell invasion by certain opportunistic pathogenic fungi, with the most comprehensive mechanistic studies focusing on Mucorales fungi, which represent important pathogens that cause invasive fungal infections that progress to sepsis in immunocompromised hosts.

Mucormycosis is a lethal invasive fungal infection caused by Mucorales fungi such as Rhizopus, predominantly affecting individuals with diabetic ketoacidosis (DKA), hematological malignancies, or those undergoing chemotherapy or immunosuppressive therapy, that results in immunocompromised states (92). Mechanistic studies have confirmed that under pathological conditions such as DKA, csGRP78 expression is significantly upregulated in host nasal epithelial cells and vascular endothelial cells. csGRP78 directly and specifically binds to the CotH3 protein on the outer wall of Mucorales fungal spores, mediating spore adhesion to and invasion of host epithelial cells and vascular endothelial cells, thereby leading to vascular invasion and tissue necrosis. This process represents the core mechanism underlying the specific infection of immunocompromised hosts by Mucorales fungi (91,105).

Research on other common pathogenic fungi indicates has not produced definitive evidence that currently confirms that Candida albicans, Aspergillus fumigatus, Cryptococcus neoformans, or Histoplasma capsulatum directly utilize host csGRP78 as an invasion receptor. Only studies on Pneumocystis jirovecii suggest that it may bind to GRP78 on the surface of lung epithelial cells, with csGRP78 potentially serving as a putative receptor for host cell adhesion, although the relevant mechanisms require further validation (93). A summary of the differential roles of GRP78 in the invasion of various pathogenic fungi is presented in Table IV (91-93,105-110).

Compared with viruses and fungi, the current evidence regarding the direct role of csGRP78 in mediating bacterial adhesion and invasion remains relatively limited. The existing research focuses primarily on bacterial infection-induced ER stress and changes in GRP78 expression in host cells, with only a few pathogens confirmed to directly interact with csGRP78 to promote the infection process (94); meanwhile, the indirect regulatory role of GRP78 in bacterial sepsis, which is equally important, has been underemphasized.

The membrane protein Mhp271 of Mycoplasma hyopneumoniae can directly and specifically bind to the NBD of host cell csGRP78, promoting mycoplasmal adhesion to and invasion of host cells, which represents an important mechanism in its infection process (94). Although Mycoplasma hyopneumoniae is a rare cause of severe sepsis in humans, this interaction provides a proof-of-concept that csGRP78 can function as a bacterial receptor. Research on other common sepsis-causing pathogens has shown that infections with Staphylococcus aureus, Escherichia coli, Pseudomonas aeruginosa, Salmonella, Mycobacterium tuberculosis, Helicobacter pylori and Streptococcus pneumoniae can induce ER stress in host cells and upregulate GRP78 expression (95-98,111-113). However, no definitive direct evidence currently confirms that these bacteria utilize host csGRP78 as an adhesion or invasion receptor.

Notably, the contribution of GRP78 to bacterial sepsis is not dependent on its role as a direct receptor; instead, its indirect regulatory effects on host inflammatory responses, phagocytic function and barrier integrity constitute a temporally ordered, functionally interdependent pathogenic sequence that drives bacterial sepsis progression. It is hypothesized that GRP78 functions as a systems-level coordinator of the failure of the host response through the following integrated sequence.

Phase I: Barrier disruption and bacterial translocation. Bacterial infection-induced ER stress contributes to the downregulation of tight junction proteins in intestinal epithelial cells, disrupting barrier function and creating an anatomical portal for bacterial translocation (111,112). Escherichia coli-derived LPS aggravates ER stress and ER stress-mediated apoptosis in ER stress-responsive IPEC-J2 cells; the crosstalk between nuclear GRP78 and p53 triggers this LPS-induced increase in apoptosis (112). Salmonella infection activates the IRE1α-UPR signaling axis via curli proteins, upregulating GRP78 expression (113). In patients with cancer, chemotherapy and radiotherapy pre-compromise mucosal integrity, while tumor-derived sGRP78 may further impair barrier repair by suppressing local immune surveillance, increasing the width of the anatomical portal and decreasing its defense.

Phase II: Innate immune dysregulation and delayed clearance. As bacteria translocate, host macrophages upregulate GRP78 in response to infection-induced ER stress. However, this upregulation paradoxically impairs rather than enhances antimicrobial function. Streptococcus pneumoniae infection induces the significant upregulation of GRP78 expression in aged lungs, which is associated with decreased NLRP3 inflammasome activation and impaired bacterial clearance by senescent macrophages (95). Additionally, ER stress-mediated GRP78 overexpression can trigger macrophage death through the PERK/ATF4/CHOP pathway, further reducing the phagocytic capacity (114).

Phase III: Inflammatory amplification and tissue injury. When the bacterial burden exceeds the blunted clearance capacity of Phase II, sustained ER stress drives the dissociation of GRP78 from UPR sensors, activating the NF-κB, MAPK and AP-1 signaling pathways and triggering excessive proinflammatory cytokine secretion (18,115). In the context of persistent ER stress, CHOP activation downstream of the PERK-eIF2α axis induces apoptosis, exacerbating tissue damage and systemic inflammation (114). Staphylococcus aureus infection activates the GRP78-EIF2α-ATF4 pathway and ER stress-autophagy axis, leading to host cell apoptosis (111). In patients with cancer, chemotherapy-induced tumor cell death releases damage-associated molecular patterns, which may synergize with bacterial pathogen-associated molecular patterns to amplify the inflammatory cytokine storm beyond the threshold observed in non-cancer sepsis.

Phase IV: Endothelial dysfunction and multiorgan failure. The sustained inflammatory milieu drives the translocation of GRP78 to endothelial cell surfaces, where csGRP78-mediated signaling disrupts vascular integrity. GRP78-induced O-GlcNAcylation of VE-cadherin compromises endothelial junctions, whereas the activation of the PERK/IRE1α pathway promotes NF-κB binding to the iNOS promoter, driving excessive nitric oxide production that induces vasodilation, hypotension and tissue hypoperfusion (114,116,117). These vascular and barrier effects culminate in the hemodynamic collapse and multiorgan dysfunction characteristic of septic shock.

Fundamental mechanistic distinction: Thus, unlike in viral and fungal infections, where csGRP78 functions as a canonical adhesion or coreceptor, csGRP78 does not appear to serve as a primary bacterial receptor for major pathogens causing sepsis in humans. Instead, GRP78 modulates host inflammatory responses, phagocytic function and epithelial barrier integrity through an indirect, temporally ordered, four-phase mechanism that coordinates the failure of the host response from the initial bacterial encounter to terminal organ dysfunction. This systems-level role represents a fundamental mechanistic distinction across pathogen classes.

A summary of the roles of GRP78 in different bacterial infections is presented in Table V (94-98,111-113,118-124), which highlights that the indirect regulatory effects of GRP78 on host immunity and barrier function are far more extensive than its direct role as a bacterial receptor and that these indirect effects are crucial for the progression of common bacterial infections to sepsis.

In summary, the existing research has fully confirmed that csGRP78 serves as a critical receptor or coreceptor for host cell invasion by multiple viruses and Mucorales fungi. Its abnormal overexpression can directly increase host susceptibility to these pathogens, providing the core pathological foundation for the subsequent progression of infection to sepsis. Although direct evidence that csGRP78 acts as a bacterial receptor is currently limited, the role of GRP78 in the progression of bacterial sepsis, the primary cause of clinical sepsis, through its indirect regulation of inflammatory responses, phagocytic function and barrier integrity is indispensable.

The regulation of proinflammatory cytokines by GRP78 is the core of its stage-dependent effects, with distinct roles for tumor-derived and host-derived GRP78.

The regulation of anti-inflammatory mediators by GRP78 primarily serves to amplify immune suppression in late sepsis, with consistent effects observed for tumor-derived and host-derived GRP78.

The regulation of chemokines (IL-8, MCP-1 and MIP-1α/β) by GRP78 is closely linked to sepsis-induced tissue inflammation, with the effects varying by the sepsis stage.

Early sepsis: Intracellular GRP78 (host-derived) acts as a positive regulator of IL-8 and MCP-1 levels, promoting endothelial inflammatory responses and leukocyte infiltration to facilitate pathogen clearance. In an LPS-induced acute lung injury model, the cleavage of intracellular GRP78 suppressed IL-8 expression and pulmonary inflammation (134) and Apelin-36 reduced LPS-induced MCP-1 release by inhibiting the GRP78/ASK1/JNK pathway (148), confirming the proinflammatory role of GRP78 in early sepsis.

Late sepsis: Excessive sGRP78 (tumor and host-derived) inhibits chemokine production, reducing leukocyte recruitment to infection sites and impairing pathogen clearance. For example, the GRP78-specific monoclonal antibody N88 reduces CCL3/CCL4 (MIP-1α/β homologues) expression in LPS-stimulated macrophages (136), whereas the inhibition of the IRE1/XBP-1 pathway (downstream of GRP78) reduces MIP-1α/β production and alleviated acute lung injury (137); these effects reflect the shift of GRP78 function towards immunosuppression in late sepsis.

This stage-specific switch in chemokine regulation by GRP78 underscores its central role in balancing inflammatory cell infiltration: promoting pathogen clearance in early sepsis but contributing to immune evasion in late sepsis.

GRP78 modulates vasoactive mediators and endothelial inflammation in a stage-dependent manner, contributing to sepsis progression.

Early sepsis: Host-derived csGRP78 and intracellular GRP78 drive vascular dysfunction and inflammatory amplification. Intracellular GRP78 activates the PERK/IRE1α pathway, promoting NF-κB binding to the iNOS promoter and excessive NO production to induce vasodilation, hypotension and tissue hypoperfusion (138). In endothelial cells, csGRP78 binds anti-GRP78 autoantibodies, activating NF-κB to upregulate ICAM-1/VCAM-1 and promoting leukocyte adhesion and transendothelial migration (116). These effects are necessary for local inflammation but, when they are excessive, contribute to systemic endothelial dysfunction.

Late sepsis: Sustained GRP78 activation exacerbates endothelial barrier disruption and multiorgan dysfunction. Excessive NO production (mediated by GRP78/iNOS) leads to irreversible vascular hyporesponsiveness, whereas persistent endothelial activation (via csGRP78) disrupts barrier integrity, which are key features of septic shock (70,149).

In patients with cancer, tumor-derived sGRP78 further exacerbates vascular dysfunction by disrupting endothelial barrier integrity, increasing the likelihood of developing septic shock compared with patients with non-cancer sepsis. Specifically, sGRP78 promotes angiogenesis and endothelial cell proliferation under physiological conditions (150,151); however, during sustained ER stress in individuals with sepsis, the cell surface translocation of GRP78 induces the O-GlcNAcylation of VE-cadherin and disrupts endothelial junctions, leading to increased vascular permeability and barrier dysfunction (117). This paradoxical shift from proangiogenic to barrier-disruptive functions contributes to the hemodynamic instability characteristic of septic shock in patients with cancer.

The regulation of ROS and MMPs by GRP78 also follows a stage-dependent pattern.

ROS regulation: In early sepsis, intracellular GRP78 (host-derived) maintains redox homeostasis by suppressing ER stress and increasing the activity of Nrf2/HO-1 antioxidant axis (139,140), mitigating oxidative damage. In late sepsis, persistent ER stress induces GRP78 dysfunction, disrupting oxidative-antioxidant equilibrium and exacerbating cellular injury and decreased GRP78 expression is correlated with the exacerbation of oxidative stress in individuals with sepsis-induced AKI (141).

MMP regulation: In early sepsis, GRP78 upregulates MMP-2/9/14 expression via the FAK-Src-JNK-c-Jun pathway, promoting extracellular matrix degradation and leukocyte infiltration (142). In late sepsis, excessive MMP activation (mediated by GRP78) contributes to tissue remodeling and multiorgan fibrosis; PI3K-γ inhibition attenuates GRP78-related ER stress and MMP-9 expression, improving pulmonary pathology in individuals with sepsis-associated acute lung injury (152).

The transcriptional activation of the GRP78-encoding gene HSPA5 is primarily mediated by the ERSE in its promoter region, where ERSE-binding transcription factors such as NF-Y, YY1, general TFII-I and ATF6 play key roles (183), with most transcriptional regulators acting by interfering with the binding of these factors to the HSPA5 promoter. For instance, genistein represses GRP78 transcription by antagonizing NF-Y/CBF binding to ERSE (170). In addition to this canonical ERSE-dependent pathway, ERSE-independent regulatory axes also serve as potential targets for GRP78 transcriptional intervention. Under pathological ER stress, ATF4 activates the HSPA5 promoter by forming a complex with ATF1 and CREB1, but in bortezomib-resistant osteosarcoma cells, ATF4 and its activators can repress GRP78 transcription via alternative mechanisms, reflecting context-dependent bidirectional regulation (158) and agents such as AR12, Kringle 5 (K5), piperine and ribociclib target this axis through distinct pathways (155,158,168).

With respect to post-transcriptional regulation, nucleic acid drugs are the most well-developed targeting agents and an in vitro study has confirmed that miR-181a directly targets the 3′-untranslated region (3′-UTR) of the GRP78 mRNA to inhibit GRP78 translation (181). Notably, transcriptional and post-transcriptional inhibitors non-selectively suppress GRP78 expression in both tumor cells and host immune/epithelial cells, posing significant feasibility risks in treating sepsis. For example, GRP78 is essential for maintaining cellular homeostasis in normal tissues; a global reduction in the level of GRP78 of 50% in whole body or specific tissues potently suppresses tumorigenesis, but requires a careful evaluation of potential side effects on normal organs (182). In the context of sepsis, where host cells rely on GRP78 to manage ER stress and maintain barrier function, non-selective inhibition may exacerbate tissue damage and impair immune cell viability (115). This finding is particularly concerning given that GRP78 levels are correlated with disease severity in sepsis patients and that both insufficient and excessive ER stress responses can be detrimental (6). Thus, these non-selective strategies are not suitable for direct application in patients with cancer with active sepsis unless they are combined with tumor-specific delivery systems.

The biological function of GRP78 can be modulated at the translational and post-translational levels primarily through direct targeting of the GRP78 protein, including blocking its functional domains, inducing conformational changes, promoting protein cleavage or degradation and inhibiting its subcellular translocation. csGRP78 represents the most feasible target for balancing antitumor and anti-infective effects, as it is selectively overexpressed on the membranes of malignant and stressed epithelial cells but minimally expressed on normal quiescent cells (17,115). This selectivity arises because normal cells retain GRP78 within the ER through KDEL-mediated retrieval, whereas cancer cells and virally infected cells display significantly higher levels of csGRP78 because of constitutive ER stress and impaired retrograde transport (17,115). This selectivity allows the targeted inhibition of tumor-associated csGRP78 without significantly impairing host GRP78 function.

Monoclonal antibodies and peptides serve as the primary targeting modalities, with monoclonal antibodies, including SAM-6, C38, C107, anti-CDT and N88, effectively blocking csGRP78 function (159-162). Importantly, these antibodies predominantly target the tumor cell marker csGRP78, inhibiting tumor progression while avoiding the direct suppression of host immune cells to reduce the risk of exacerbating sepsis-related immunosuppression. For example, the GRP78-neutralizing human monoclonal antibody hMAb159 specifically blocks csGRP78-mediated pathogen invasion without affecting the chaperone function of intracellular GRP78 in host cells (73), making it a promising candidate for treating cancer-associated sepsis.

While monoclonal antibodies represent a well-established class of csGRP78-targeting agents, peptide-based therapeutics have also been widely developed for this purpose. Pep42, a 13-amino acid cyclic peptide, specifically binds csGRP78 on tumor cells and mediates its lysosomal internalization, serving as a tumor-targeted drug delivery carrier (163,184), whereas other peptides exert antitumor effects by targeting different csGRP78 or intracellular GRP78 domains (164-167); however, the effects of intracellular GRP78 inhibitors require careful consideration in treating sepsis: Inhibiting intracellular GRP78 in host cells may disrupt ER homeostasis and exacerbate inflammatory dysregulation, particularly in early sepsis, in which host-derived intracellular GRP78 is critical for controlling the inflammatory cytokine storm.

There are two major classes of inhibitors that target intracellular GRP78 that have been developed: Natural products and synthetic small molecules. Natural products and synthetic small molecules are the main inhibitors targeting intracellular GRP78 domains, with honokiol showing promise as a treatment for intracranial diseases because of its ability to cross the blood-brain barrier (153,154,156,157,169,171-174). In addition to inhibitors targeting specific domains, two alternative strategies have been explored to disrupt GRP78 function: inducing protein cleavage and triggering conformational changes. Modified bacterial toxins (such as SubAB) induce site-specific GRP78 cleavage to inactivate it (177), whereas metal-based drugs modulate GRP78 via conformational changes or promoter inhibition, with NKP-1339 entering clinical trials as a treatment for solid tumors (175,176). However, these intracellular inhibitors lack tumor selectivity and may impair host cell function in individuals with sepsis; their clinical application requires tumor-specific delivery systems to reduce off-target toxicity.

GRP78 is proposed as a pivotal molecular nexus that may connect tumor progression with increased susceptibility to sepsis in patients with cancer. Targeting GRP78 presents a distinctive dual therapeutic potential within this population, but its clinical feasibility depends on addressing the 'double-edged sword' effect through stage-specific intervention and origin-specific delivery.

The aforementioned mechanistic analysis and stage-origin framework (Balancing antitumor and anti-infective effects: Timing and precision delivery in patients with cancer-associated sepsis) can be translated into a concrete, prioritized clinical development roadmap. Three criteria guide the ranking: i) Tumor selectivity (agents must spare host GRP78 to avoid exacerbating the infection); (ii) mechanistic clarity (agents with validated target engagement in human systems are preferred over preclinical leads) and (iii) regulatory feasibility (agents with an existing IND/IMPD status or prior oncology phase I data are prioritized for repurposing as sepsis treatments if their safety profile permits acute administration).