Gastric cancer (GC) represents a prominent public health concern globally, characterized by limited effective treatment options, poor prognosis and high mortality rates (1). Anti-GC treatments, which are primarily based on chemotherapy, radiation therapy and targeted therapy, face a major challenge in the form of acquired resistance (2). GC cells acquire resistance through a range of mechanisms and associated signaling, all involving both intrinsic and extrinsic factors (3). According to the Lauren classification, GC is categorized into two major histopathological subtypes with distinct biological behaviors: Intestinal-type and diffuse-type (4). Intestinal-type GC, accounting for 50–60% of cases, arises from intestinal metaplasia (a premalignant lesion), exhibits glandular differentiation and is associated with environmental risk factors [such as Helicobacter pylori (H. pylori) infection, high-salt diet and smoking] (5). It typically presents as an exophytic or ulcerative mass in the distal stomach, progresses slowly and has a relatively favorable prognosis (5). By contrast, diffuse-type GC (30–40% of cases) lacks glandular structure, is characterized by signet ring cells with intracellular mucin accumulation and is linked to genetic predispositions [such as cadherin-1 (CDH1) mutations] (6). It invades diffusely through the gastric wall (linitis plastica), has early metastatic potential and confers a worse outcome. A third subtype, mixed-type GC (10–15% of cases), combines features of both intestinal and diffuse types and exhibits intermediate clinical behavior (6).

GC progression follows a well-defined natural history, from premalignant lesions (gastric atrophy, intestinal metaplasia and dysplasia) to early stage localized tumors, and ultimately to advanced disease with lymph node (LN) and distant metastasis. Multiple factors modulate this process, including: i) Microenvironment (ME) factors: Beyond hypoxia, H. pylori infection (the strongest risk factor) induces chronic inflammation, oxidative stress and epithelial dysregulation, which synergize with hypoxia-inducible factors (HIFs) to promote carcinogenesis; ii) genetic/epigenetic alterations: Mutations in TP53, CDH1 and epidermal growth factor receptor 2 (ERBB2) and microsatellite instability (MSI) contribute to subtype-specific progression, with HIFs interacting with these pathways to enhance malignancy; and iii) lifestyle and host factors: Obesity, alcohol consumption and immune dysregulation further exacerbate GC development by altering tumor ME (TME) hypoxia and HIF activation.

Pathological staging of GC adheres to the American Joint Committee on Cancer/Union for International Cancer Control/TNM system (8th edition) (7), which classifies tumors based on primary tumor invasion depth (T), lymph node involvement (N) and distant metastasis (M) (7). Pathological staging (pTNM) is the gold standard for prognosis, with pT1 (tumor invading mucosa/submucosa) and pT2 (invading muscularis propria) defining early-stage GC (I–II), and pT3 (serosa invasion) and pT4 (adjacent organ invasion) indicating locally advanced disease (III) (8). LN involvement is stratified as pN0 (no LN metastasis), pN1 (1–2 positive LNs), pN2 (3–6 positive LNs) and pN3 (≥7 positive LNs), with pN3 indicating high metastatic potential (8). Clinical staging (cTNM), based on preoperative imaging and endoscopy, guides treatment selection but is less accurate than pTNM, particularly for LN assessment (9). Clinically, early-stage GC (cI–II) is curable with surgery, while advanced-stage GC (cIII–IV) requires multimodal therapy (3). Notably, HIF expression is associated with TNM stage: HIF-1α upregulation is detected in 40–70% of GC cases, with higher levels in pT3-pT4 tumors, pN2-pN3 LN status and M1 disease, making it an independent prognostic marker (10).

Anti-GC treatments, primarily based on chemotherapy, radiation therapy, targeted therapy and immunotherapy, face a major challenge in acquired resistance. GC cells acquire resistance through intrinsic (genetic mutations and metabolic reprogramming) and extrinsic (TME hypoxia and immunosuppression) mechanisms, all involving HIF-mediated signaling (11). For most patients with end-stage cancer, the primary cause of treatment failure is resistance to cancer therapy, and primary or acquired drug resistance particularly acts as a major impediment in clinical oncology (11). Therefore, studying drug resistance mechanisms is of equal importance to drug development, and both pharmacological factors, including insufficient drug concentration at the tumor site, and cellular factors, such as aberrant activation of signal transducer and activator of transcription 3 (STAT3) signaling, enhanced tumor cell stemness, epithelial-mesenchymal transition (EMT) and overexpression of ATP-binding cassette (ABC) transporters, can contribute to clinical resistance in gastric cancer (12). The mechanisms governing drug resistance in tumors are precise yet complex and multifactorial, and they can be grouped into three categories: i) Inadequacies in pharmacokinetic properties; ii) intrinsic factors of tumor cells; and iii) external conditions of tumor cells in the TME (13).

Accumulating evidence has demonstrated that the TME drives cancer progression through multiple mechanisms, with a prominent role in mediating therapeutic resistance (14). On the one hand, the TME impairs drug penetration, confers surviving cancer cells with proliferative and antiapoptotic properties to facilitate therapeutic resistance, and induces common morphological alterations of the disease (15). On the other hand, it is enriched with soluble factors secreted by both tumor and stromal cells, which in turn contribute to aberrant cell proliferation, pathological angiogenesis, tumor metastasis and the development of drug resistance (16). As the rapid and uncontrolled proliferation of tumor cells restricts oxygen availability, leading to insufficient blood supply or hypoxia, this condition has become a typical ME feature in nearly all solid tumors (16). Hypoxia elicits intratumoral oxygen gradients, and subsequently contributes to the plasticity and heterogeneity of tumors while enhancing the emergence of more aggressive, metastatic phenotypic traits (11). Moreover, the TME undergoes remodeling under hypoxic conditions, which in turn affects the stemness, chemoresistance, epithelial-mesenchymal transition (EMT) and angiogenesis of GC cells and tissues (Fig. 1) (17–19). In this process, the increased expression of HIFs is a pivotal hallmark. The HIF family consists of HIF-1, HIF-2 and HIF-3, and serves a central role in cellular mechanisms triggered in response to hypoxia (20,21).

HIF-1, the most important component of the HIF family, is predominantly made up of two subunits, namely HIF-1α and HIF-1β (22). Under normal oxygen concentrations, HIF-1α undergoes degradation and fails to maintain stable expression, whereas under hypoxic conditions, it translocates into the nucleus and dimerizes with HIF-1β to promote the transcription of downstream genes (Fig. 2) (23). The specific mechanism is as follows: Under normoxic conditions, HIF-1α undergoes prolyl hydroxylation catalyzed by prolyl hydroxylase (PHD). This modified HIF-1α is subsequently recognized and bound by the von Hippel-Lindau tumor suppressor protein and upon this binding, is ubiquitinated and ultimately degraded (24–26). Under hypoxic conditions, PHD inactivation blocks oxygen-dependent prolyl hydroxylation, which inhibits HIF-1α degradation; the accumulated HIF-1α subsequently enters the nucleus, combines with HIF-1β to form a dimer, and this dimer regulates the expression of hypoxia-related genes with the participation of transcriptional co-activators such as histone acetyltransferase p300, finally facilitating cellular adaptation to hypoxia (27–31).

HIF-2 is composed of HIF-2α and HIF-2β, with HIF-2α serving as the primary functional subunit that is abundant in tissues including vascular endothelial cells and fetal lung fibroblasts, and upon activation, HIF-2α binds to aryl hydrocarbon receptor nuclear translocator (ARNT) to form a heterodimer (32,33). Hypoxia-inducible factor 3 (HIF-3) is a relatively understudied member of the HIF gene family, and it is composed of HIF-3α and HIF-3β subunits. The HIF-3α gene undergoes complex transcriptional regulation, generating multiple alternatively spliced HIF-3α variants through the use of different promoters and transcription initiation sites (34). These variants exhibit differential expression patterns, which are tightly regulated not only by hypoxia but also by multiple non-hypoxic factors (34). Notably, these non-hypoxic regulatory factors include pro-inflammatory cytokines (which regulate HIF-3α via NF-κB-dependent epigenetic modifications), insulin-mediated PI3K/protein kinase B (AKT) signaling (which modulates HIF-3α stability through phosphorylation) and the von Hippel-Lindau (VHL) E3 ubiquitin ligase complex (which targets specific HIF-3α variants for ubiquitination and degradation in an oxygen-dependent manner) (34). Full-length HIF-3α protein functions as an oxygen-regulated transcriptional activator (35).

In 2003, HIF-1α was first identified as exhibiting stable expression in GC tissues and was involved in the initiation and progression of GC (36). Since this initial discovery, numerous subsequent investigations have confirmed that HIF exerts a regulatory effect on the initiation and progression of GC and the development of HIF-targeted agents could represent a promising therapeutic strategy for advanced GC (37–40). Therefore, the present review focuses on the role of HIF in GC, specifically addressing its regulatory effects on GC cell proliferation, metastasis, apoptosis, drug resistance, angiogenesis, stemness and metabolism, and also covers several HIF-targeted therapeutic agents for GC.

Tumor cells induce the formation of new blood vessels as an adaptive response to low oxygen and nutrient levels, a process termed de novo angiogenesis (11). The newly generated blood vessels exhibit leakiness due to their discontinuous endothelium and impaired lymphatic drainage, ultimately leading to vascular hyperpermeability and increased permeation (41). Hence, hypoxia induces vascular leakage and dysregulated lymphatic drainage in the tumor, ultimately resulting in elevated interstitial fluid pressure (42). The TME denotes the local biological environment where solid tumors reside, which comprises cancer cells and adjacent stromal cells, specifically normal host cells (such as fibroblasts, various immune cells and blood/lymphatic cells) recruited by cancer cells and embedded in densely packed extracellular matrix (43–45). The secondary development of adverse metabolic and physical MEs leads to an imbalance between the positive and negative regulators that govern the activation and dysregulation of angiogenesis, desmoplasia and inflammation (44,46–48). Most neoplasms harbor hypoxic regions, and the formation of an abnormal vasculature alongside a hypoxic ME promotes aberrant angiogenesis, desmoplasia and inflammation, all of which contribute to tumor progression and therapeutic resistance (49,50). A previous review highlighted that cancers evade host regulatory mechanisms and disrupt systemic homeostasis by secreting a spectrum of neurohormonal mediators (including cytokines, neurotransmitters and pituitary hormones) and immune factors, as validated in both human and animal models (51). It is hypothesized that these tumor-derived molecules enable bidirectional crosstalk with central neuroendocrine axes (such as hypothalamic-pituitary-adrenal and thyroid axes) and peripheral autonomic/sensory nerves, allowing tumors to hijack host homeostatic regulation to support their progression (51). This paradigm suggests that malignant cells actively manipulate central neuroendocrine and immune systems, reshaping systemic balance at the expense of the host, to facilitate tumor expansion (51).

HIF-1α orchestrates hypoxia-induced signaling that regulates multiple steps of the metabolic substrate transport cascade, mainly glucose and lactate transport, to support cellular adaptation to hypoxic microenvironments (52). Research findings have demonstrated that cancer-associated fibroblasts (CAFs) and myeloid cells facilitate tumor metastasis (53). Under hypoxic conditions, activated HIF-1α enhances the activity of Snail and Twist, two transcription factors that downregulate E-cadherin expression and drive EMT (54–56). Of note, although EMT-associated signaling is not required for the metastatic process, it can enhance multiple malignant traits of tumor cells, including invasion, senescence, cancer stem cell-like phenotype and chemoresistance (57). HIF-1α can additionally modulate the expression of enzymes responsible for collagen fiber polymerization and alignment regulation, as well as integrin activity, to promote cancer migration (52). Moreover, hypoxia induces leakiness and compression of blood and lymphatic vessels, a process mediated by HIF-regulated factors including angiopoietin-2, vascular endothelial growth factor (VEGF) and angiopoietin-like 4, thereby facilitating the transmigration of metastatic cancer cells through the vessel wall (58).

The hypoxic ME supports glycolysis and subsequent lactic acid generation mediated by glycolytic key enzymes and lactate dehydrogenase A; this excess lactic acid accumulation leads to an acidic extracellular pH (59–61). Moreover, HIF can facilitate the reverse conversion of carbon dioxide and water, generated via the activation of carbonic anhydrase IX or XII into bicarbonate ions (HCO₃⁻). HCO₃⁻ then diffuses across the cell membrane, leading to HCO₃⁻ accumulation in the TME and a subsequent reduction in extracellular pH (62). Numerous studies have demonstrated that reduced intracellular pH of endosomes and lysosomes in tumor cells can facilitate tumor metastasis via protease activation (42,63). Indeed, changes in extracellular pH induce drug resistance via suppressing cellular and humoral immune functions, as acidic pH is prevalent at sites of inflammation and other immunologically active regions (64–67). A reduction in pH mainly inhibits the chemotaxis, respiratory activity and bactericidal ability of polymorphonuclear leukocytes (68–70). Under acidic pH conditions, impaired cytotoxicity and proliferation of lymphocytes have been reported, and similarly, cytotoxic T lymphocytes exhibit decreased lysis of various tumor cell lines in this acidic extracellular environment, while neutralization of T cell effector function and tumor acidity can improve the response to immunotherapy (63,71–73). Furthermore, studies focusing on macrophages and eosinophils have indicated that acidic conditions induce the activation of complement proteins and the alternative complement pathway, which is accompanied by increased binding of antibodies to leukocytes under lower pH (63,72,74).

Notably, reactive oxygen species (ROS) levels are demonstrated to be elevated in cancer cells under hypoxic conditions (75). Decreased oxygen utilization impairs electron transfer through the mitochondrial electron transport chain (ETC) complexes, which in turn promotes electron leakage from the ETC and ultimately results in the overproduction of ROS (76). Moreover, excessive ROS production disrupts genomic stability and impairs the function of DNA repair pathways (77). ROS are further capable of inducing cell survival or apoptosis through a mechanism known as oxidative stress, thereby contributing to enhanced cytotoxicity and apoptosis (78). Notably, at high concentrations (10–30 µM), ROS can induce damage to cellular biomolecules including proteins, DNA and RNA, and trigger mutations that either drive carcinogenesis in normal cells or confer multidrug resistance (MDR) in cancer cells (79). However, most cancer cells still survive under internal oxidative stress, hence avoiding apoptosis and developing resistance to chemotherapy (80). Elevated ROS exposure can drive cancer cell resistance via activating redox-sensitive transcription factors, including nuclear factor κB nuclear factor (erythroid-derived 2)-like factor 2, c-Jun and HIF-1α (80). Subsequently, the activation of these genes enhances the activation of the antioxidant system and promotes the expression of cell survival proteins (80). In addition, ROS promote the transition from apoptosis to autophagy in methotrexate-resistant choriocarcinoma Jeg-3 cells, thereby supporting the survival of these cells against methotrexate (81). ROS can also stimulate the differentiation of cancer stem cells, thus promoting EMT and inducing metabolic reprogramming involved in the resistance of cancer cells (79).

Hypoxic stress induces immunosuppression through regulating angiogenesis, as well as promoting immune evasion and tumor resistance (82–84). Notably, macrophages serve as a key component of the immune infiltrate in solid tumors via their differentiation into tumor-associated macrophages (TAMs), which are preferentially localized in hypoxic regions of tumors (85). Furthermore, cytokines derived from tumors can induce the conversion of TAMs into polarized type 2 (M2) macrophages, which exhibit enhanced immunosuppressive activity and thereby contribute to tumor progression (86–88). Additionally, myeloid-derived suppressor cells (MDSCs) directly contribute to immune tolerance, and in hypoxic zones, HIF-1 directly modulates the differentiation and function of MDSCs with these tumor-derived MDSCs exhibiting greater immunosuppressive activity than splenic MDSCs (89).

Previous studies have shown the upregulation of the expression of programmed death-ligand 1 (PD-L1) under hypoxia (89–91). HIF-1 serves as a key regulator of both PD-L1 mRNA and protein expression, specifically by directly binding to a hypoxia response element (HRE) within the proximal promoter of PD-L1 (89). The originally elevated immunosuppressive function of tumor derived MDSCs under hypoxia was found to be abrogated following PD-L1 blockade. Consistent with PD-L1 blockade, the hypoxia-driven upregulation of IL-6 and IL-10 in MDSCs was notably attenuated (92). Currently, immunotherapeutic strategies that elicit antitumor immunity exhibit limited efficacy due to the diverse mechanisms by which tumors evade immunosurveillance (92). Antibody blockade of the T-cell immune checkpoint receptors programmed cell death protein-1 (PD-1) and cytotoxic T-lymphocyte-associated protein 4 exhibit poor efficacy in certain tumors due to sparse or absent T cells in the TM, and hypoxia-driven modulation of T-cell exclusion and apoptosis helps sustain this state (93–95). While T cells can enter hypoxic tumors, hypoxia-driven acidification of the extracellular environment impairs their ability to proliferate or exert cytotoxic effector functions (72,96). Taken together, tumor hypoxia predicts poor outcomes across numerous types of cancer, and hypoxia plays a key role in establishing and maintaining tumor immune privilege or resistance to immunotherapy (97).

Small-molecule drugs (SMDs) are typically defined as organic compounds with a molecular weight generally not exceeding 1,000 Da and most of them possess physicochemical properties such as good cell membrane permeability and structural modifiability, which lay the foundation for their subsequent biological activity (186). Due to their favorable pharmacokinetic characteristics (such as easy absorption, distribution and metabolic adjustability) and relatively low production costs, SMDs have been widely applied in the clinical treatment of various diseases, including tumors, cardiovascular disorders and infectious diseases, and have long occupied a core position in therapeutic regimens (187). The theoretical system supporting SMD research and development which covers key fields such as medicinal chemistry, structure-activity relationship analysis and high-throughput screening has become increasingly mature, providing solid technical support for the efficient discovery and optimization of novel small-molecule therapeutic agents (188–190).

Numerous SMDs capable of suppressing the progression of GC through HIF targeting have been identified (Table I). A previous study demonstrated that apigenin, a flavonoid component present in traditional medicines, fruits and vegetables, inhibits HIF-1α-induced autophagy-related cell death (191). Low-dose tipifarnib-a non-peptidomimetic quinolinone farnesyltransferase inhibitor (FTI) that exerts antineoplastic effects by inhibiting protein farnesylation, suppressing mTOR signaling, and reducing ROS levels-inhibits tumors by suppressing the expression of HIF-1α, and dextran sulphate-a sulfated polysaccharide (anionic derivative of dextran) with anticoagulant, antiviral, and protein-sequestering properties-can inhibit EMT in GC cells by inhibiting the expression of HIF (192,193). A study constructed R8-modified vinorelbine-plus-schisandrin B liposomes, validated via in vitro experiments on BGC-823 cells and in vivo experiments on nude mice bearing BGC-823 cell xenografts, were shown to synergistically induce GC apoptosis, enhance tumor cell targeting and inhibit GC metastasis by downregulating HIF-1α, thereby exerting antitumor effects and providing a safe and effective therapeutic strategy for GC (194). Moreover, numerous small-molecule therapeutic agents exert an inhibitory effect on GC progression by targeting HIF (195–201). Despite the identification of numerous small-molecule agents that inhibit GC progression by targeting HIF, none have yet translated to clinical application, highlighting the need for additional basic and clinical research.

GC development and progression are driven by the interplay of environmental, genetic, microenvironmental and host factors, all of which interact with HIF-mediated hypoxia responses.

The present review systematically synthesizes the regulatory roles, molecular mechanisms and therapeutic potential of HIFs in GC, a malignancy with high global morbidity and mortality and suboptimal outcomes for advanced-stage patients. First, hypoxia, an iconic hallmark of the TME in GC, drives TME remodeling by inducing acidification ROS accumulation and immunosuppression (such as M2 polarization of TAMs, MDSC recruitment and PD-L1 upregulation) and aberrant angiogenesis, all of which converge to promote GC progression and therapeutic resistance (11,14). Central to this hypoxic response is the HIF family, whose three subtypes (HIF-1, HIF-2, HIF-3) exhibit distinct structural features and functional heterogeneity in GC. HIF-1, the most well-characterized subtype, exerts a pleiotropic oncogenic role in GC: Its α-subunit (HIF-1α) regulates GC cell proliferation via the HYPAL/miR-431-5p/CDK14 or HIF-1α/miR-17-5p/PDCD4 axis, drives EMT through direct transactivation of LXRα or exosomal miR-301a-3p secretion, enhances chemoresistance by modulating PKM1 or MDR1/P-gp, promotes angiogenesis via VEGF-A or β-catenin/VEGF signaling and supports aerobic glycolysis (Warburg effect) through the FOXO4/LDHA or circ-MAT2B/miR-515-5p axis (106,113,120,121). By contrast, HIF-2 (primarily HIF-2α encoded by EPAS1) remains less well studied in GC; existing evidence links it to vascular endothelial function and GC cell metabolism, but its precise role in proliferation, metastasis or resistance, especially across GC subtypes (intestinal vs. diffuse), remains elusive (226–228). HIF-3, the least explored subtype, exhibits context-dependent activity; its splice variant IPAS competitively inhibits HIF-1α-mediated transactivation of pro-tumor genes, yet some studies suggest pro-metastatic effects via uncharacterized signaling axes, highlighting unresolved controversies in the functional role of HIF-3 (35,184,185,229–233). Finally, a panel of small-molecule agents (such as apigenin, tipifarnib and schisandrin B) have been summarized that target HIFs to suppress GC progression, although all remain confined to preclinical models without clinical translation.

The findings presented in the present review reinforce the centrality of HIFs as integrators of hypoxic TME signals and GC malignant phenotypes, aligning with the broader consensus that hypoxia-driven HIF activation is a non-negotiable step in solid tumor progression (10,11). Induction of melanogenesis robustly upregulates HIF-1α expression and its downstream target genes related to angiogenesis and glycolysis, along with a subset of HIF-1-independent genes, in melanoma cells and tissues, highlighting the critical role of HIF-1α in mediating the metabolic regulatory effects of specific cellular processes (234). A critical insight is the bidirectional crosstalk between HIFs and the TME: HIFs not only respond to hypoxia but also actively reshape the TME. For example, HIF-1α-induced lactate production (via LDHA) acidifies the extracellular ME, which in turn inhibits T-cell cytotoxicity and enhances MDSC immunosuppressive activity; concurrently, ROS generated by mitochondrial dysfunction under hypoxia stabilizes HIF-1α, creating a positive feedback loop that amplifies pro-tumor signaling (235–237). This crosstalk explains why targeting HIFs may simultaneously disrupt multiple hallmarks of GC (such as angiogenesis, immune evasion and metabolic reprogramming) rather than acting on a single pathway.

Another notable observation is the subtype-specific functional diversity of HIFs. HIF-1α is widely regarded as a universal oncogenic driver in GC, consistent with its overexpression in most GC tissues and association with poor prognosis (34). By contrast, HIF-2α exhibits tissue-specific expression (such as vascular endothelial cells) and may play a more context-dependent role. For instance, it promotes angiogenesis in GC via VEGF but has also been linked to differentiation in certain cell types (34). HIF-3α, meanwhile, represents a ‘double-edged sword’; its full-length isoform may act as a transcriptional activator, while splice variants such as IPAS antagonize HIF-1α (34). This heterogeneity underscores the need for subtype-specific targeting strategies, as pan-HIF inhibitors may disrupt physiological hypoxia responses (such as wound healing) and cause off-target toxicity which is a major barrier to clinical translation. From a therapeutic perspective, the preclinical efficacy of HIF-targeted small molecules (Table I) validates HIFs as viable targets for GC. For example, low-dose tipifarnib inhibits HIF-1α without affecting Ras signaling, addressing the toxicity concerns of earlier FTIs; R8-modified vinorelbine-schisandrin B liposomes enhance tumor targeting while downregulating HIF-1α, overcoming the poor bioavailability of numerous small molecules (192,194). However, a critical translational gap persists as no HIF-targeted agent has entered clinical trials for GC, despite the Food and Drug Administration approval of Welireg (a HIF-2α inhibitor) for von Hippel-Lindau syndrome. This gap likely stems from two challenges: i) The lack of predictive biomarkers to identify patients most likely to benefit (such as HIF-1α-high vs. HIF-2α-high GC); and ii) the potential for adaptive resistance, as HIF inhibition may activate compensatory pathways (such as PI3K/Akt/mTOR). Future studies should prioritize combinatorial strategies, for example, HIF inhibitors combined with immune checkpoint blockers given that HIF-1α regulates PD-L1 expression; or HIF inhibitors plus anti-angiogenic agents (such as bevacizumab), to synergistically disrupt the vascular niche.

While the present review discusses the current state of HIF research in GC, it is important to acknowledge several limitations that reflect broader gaps in the field. First, the evidence base for HIF-2α and HIF-3α in GC remains sparse and heterogeneous. Most studies on HIF-2α focus on other cancers (such as cervical cancer and ESCC), and GC-specific data are limited to in vitro experiments with a narrow panel of cell lines (such as BGC-823or SGC-7901). Similarly, HIF-3α studies in GC are confined to small-scale tissue samples or cell models, with conflicting reports on its pro- vs. antitumor roles. This paucity of data limits our ability to draw definitive conclusions about these subtypes, emphasizing the need for more GC-specific research. Second, the review focuses primarily on HIF-mediated mechanisms in generic GC, overlooking the profound heterogeneity of the disease. GC is classified into distinct histological (intestinal, diffuse and mixed) and molecular subtypes, and HIF expression and function may vary across subtypes. For example, diffuse-type GC is characterized by EMT and high metastatic potential, but it remains unclear whether HIF-1α serves a more prominent role in this subtype than in intestinal-type GC. This lack of subtype-specific analysis limits the clinical relevance of the present review, as personalized therapy requires understanding HIF biology in distinct GC subsets. Third, the discussion of SMDs is restricted to preclinical studies, with no consideration of pharmacokinetic and pharmacodynamic challenges or clinical safety. Numerous HIF inhibitors exhibit poor solubility, short half-lives or off-target effects (such as inhibiting PHDs involved in collagen synthesis), which may explain their failure to advance to clinical trials. Additionally, the review does not address the potential for HIF-independent hypoxia responses (such as AMPK activation or autophagy), which may contribute to resistance to HIF-targeted therapy and warrants further exploration. Finally, the review relies heavily on in vitro and xenograft models, which poorly recapitulate the human GC TME. Xenograft models use immunocompromised mice, precluding analysis of HIF-mediated immune interactions (such as T-cell exhaustion or MDSC recruitment) (14); 3D cell culture models, while more physiologically relevant, are underutilized in HIF-GC research. These model limitations may lead to overestimation of HIF inhibitor efficacy, highlighting the need for more translational models (such as patient-derived xenografts, organoids) in future studies.

In summary, the present review highlights that HIFs, particularly HIF-1α, play a central role in GC progression by integrating hypoxic TME signals to regulate proliferation, metastasis, metabolism and immune evasion. While HIF-2α and HIF-3α remain less well understood, their subtype-specific functions suggest they may represent untapped targets. Despite notable preclinical progress in developing HIF-targeted small molecules, translational challenges (such as lack of biomarkers and adaptive resistance) and gaps in our understanding of HIF biology (such as subtype heterogeneity and pathway crosstalk) persist. Addressing these limitations through future research will be critical to realizing the potential of HIF-targeted therapy as a novel strategy for improving outcomes in patients with GC.