1 Introduction

Digestive tract tumors, including gastric cancer, esophageal cancer, hepatocellular carcinoma (HCC), colorectal cancer (CRC), pancreatic cancer, cholangiocarcinoma, and neuroendocrine tumors, represent a significant global health burden due to their high incidence and mortality rates. In China, the incidence and mortality of these cancers are notably higher than global averages [1, 2]. Despite advances in conventional therapies like surgery, radiotherapy, and chemotherapy, along with the emergence of immunotherapy and targeted therapies, the prognosis for many patients remains poor, particularly because of challenges in early diagnosis, treatment resistance, and tumor recurrence. Consequently, there is an urgent need for novel therapeutic strategies and a deeper understanding of the underlying molecular mechanisms driving cancer progression and treatment failure [3,4,5,6,7].

Disulfidptosis, a recently discovered regulated form of cell death, has emerged as an important player in oncology. First described by Liu et al., disulfidptosis is characterized by the accumulation of disulfide bonds under glucose-deprivation stress, particularly in cancer cells with high SLC7A11 expression. This form of cell death is driven by the depletion of NADPH, disrupting the cystine-to-cysteine reduction process, leading to disulfide stress, cytoskeletal collapse, and ultimately, cell death [8,9,10]. Tumor cells often overexpress SLC7A11 to maintain glutathione (GSH) levels and counteract oxidative stress, making this pathway a critical vulnerability in cancer cells [11,12,13]. Recent studies have demonstrated that disulfidptosis-related genes (DRGs) play key roles in metabolic reprogramming, immune modulation, and therapeutic resistance, influencing tumor progression and treatment responses in digestive tract cancers. For example, genes such as SLC7A11, RPN1, and NCKAP1 have been linked to immune infiltration, modulation of the tumor microenvironment (TME), and the regulation of chemoresistance [14,15,16,17]. Emerging research suggests that targeting disulfidptosis pathways could offer promising therapeutic interventions. Bioinformatics-driven studies highlight agents like Bosutinib and Sorafenib as potential candidates for clinical application [15]. This review aims to provide an updated synthesis of the latest advances in disulfidptosis research, focusing on its molecular mechanisms, clinical significance, and therapeutic potential, as well as its prognostic predictive effects in digestive tract tumors. By exploring the integration of DRGs into metabolic regulation and immune response modulation, we offer new perspectives on developing innovative therapies and personalized treatment strategies for these malignancies (Fig. 1).

Fig. 1
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TOC diagram for this review

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2 The mechanisms of disulfidptosis

2.1 The mechanisms and key pathways of disulfidptosis

In the 1980s, researchers discovered that certain drugs and chemicals could cause the accumulation of disulfide bonds, leading to cell death. Recently, the Gan Boyi team characterized this novel form of cell death, naming it “disulfidptosis” [8]. Their research showed that cells with high SLC7A11 expression are more susceptible to death under glucose deprivation. This susceptibility is primarily due to reduced glycolysis under glucose-starved conditions, resulting in insufficient NADPH. Without adequate NADPH, cystine cannot be reduced to cysteine, causing an accumulation of disulfide bonds and inducing disulfide stress. Disulfide bonds interact with the actin cytoskeleton, and the cross-linking of actin with cytoskeletal proteins can cause the breakdown of the actin structure, ultimately resulting in cell death (Fig. 2). Genes promoting disulfidptosis include OXSM, GYS1, NUBPL, NDUFA11, LRPPRC, and NDUFS1, while inhibitory genes include SLC7A11, SLC3A2, RPN1, and NCKAP1.

Fig. 2
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The diagram of the disulfidptosis mechanism. In SLC7A11 high-expressing cells, under glucose-deficient conditions, NADPH is insufficient for cystine to be reduced to cysteine, inducing disulfidptosis. (Created in BioRender.com)

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The core pathway of disulfidptosis involves multiple key regulatory factors and complex biological processes. Current research indicates that it primarily affects the actin cytoskeleton via the Rac-WAVE regulatory complex (WRC), resulting in abnormal disulfide bond formation, which disrupts the actin network structure and induces cell death. Gene Ontology (GO) enrichment analysis has shown that, under glucose starvation conditions, disulfide bond processes are mainly enriched in biological processes related to the actin cytoskeleton and cell adhesion [8]. NCK Associated Protein 1 (NCKAP1), a critical component of the WRC, is essential for regulating its function, as inhibiting NCKAP1 leads to a marked reduction in disulfidptosis occurrence [18, 19]. Additionally, redox equilibrium is another important factor in disulfidptosis. Cells with elevated SLC7A11 expression are more vulnerable to disulfidptosis when exposed to hydrogen peroxide (H2O2) or upon inhibition of thioredoxin reductase 1(TXNRD1) [20,21,22]. Additionally, the NF-κB and JNK signaling pathways play a role in both the occurrence and progression of disulfidptosis [23, 24]. These discoveries reveal the intricate mechanisms of disulfidptosis, providing valuable insights into cell death and emphasizing the necessity for further exploration of the various biological processes involved.

2.2 The relationship between disulfidptosis and other forms of cell death

Cell death is a fundamental physiological process essential for the survival and development of all organisms. It is generally categorized into two types: programmed cell death (PCD) and accidental cell death (ACD). PCD is a tightly regulated process controlled by intracellular signaling pathways that determine cell fate, whereas ACD results from external physical or chemical damage without involving intrinsic signaling mechanisms. Recent research has identified several forms of cell death associated with metabolic imbalances, including nutrient deficiencies and the excessive accumulation of metals such as iron and copper. These forms, collectively referred to as metabolic cell death, include ferroptosis, cuproptosis, and disulfidptosis [8,9,10].

Ferroptosis, an iron-dependent form of cell death, is characterized by lipid peroxidation driven by the accumulation of reactive oxygen species (ROS). Key regulators of ferroptosis include glutathione (GSH) and glutathione peroxidase 4 (GPX4), both of which play central roles in mitigating oxidative damage (Fig. 3) [9]. SLC7A11, which is a critical component of the cystine/glutamate antiporter system (System xc⁻), mediates cystine uptake and its subsequent conversion to cysteine for GSH synthesis. This process serves not only as a key regulatory pathway for ferroptosis but also links ferroptosis to disulfidptosis. Under conditions of NADPH depletion, excessive cysteine accumulation promotes disulfide bond formation, thereby triggering disulfidptosis. Conversely, GSH depletion weakens antioxidant defenses, exacerbating ferroptosis. The dual role of SLC7A11 in both ferroptosis and disulfidptosis underscores its pivotal function in regulating cellular responses to metabolic stress. These findings highlight SLC7A11 as a central node connecting ferroptosis, disulfidptosis, and the cellular antioxidant system, providing valuable insights into metabolic cell death and its therapeutic potential in disease treatment (Fig. 4) [8, 9].

Fig. 3
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The diagram of the ferroptosis mechanism. The primary mechanism of ferroptosis involves the catalytic peroxidation of highly expressed unsaturated fatty acids on the cell membrane, driven by divalent iron or lipoxygenases, ultimately leading to cell death. Furthermore, this process is marked by a reduction in GPX4, a key regulatory enzyme of the antioxidant system, specifically the glutathione system. (1) GPX4 inactivation due to GSH depletion; (2) Direct inactivation of GPX4; (3) Iron ion uptake and reduction: the introduction of iron ions into the cell, ensuring the abundant presence of ferrous iron (Fe2⁺), which initiates lipid peroxidation through the Fenton reaction. (Created in BioRender.com)

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Fig. 4
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The Relationship Between Disulfidptosis and Other Forms of Cell Death. (1) Under glucose deprivation, insufficient NADPH production leads to excessive accumulation of disulfide bonds within cells, thereby triggering disulfidptosis. (2) Excessive accumulation of ROS induces lipid peroxidation, which subsequently triggers ferroptosis. (3) GSH promotes the production of GPX4, maintaining intracellular redox balance, suppressing ROS production, and consequently preventing ferroptosis. (4) Excessive accumulation of copper ions (Cu⁺) generates large amounts of ROS via the Fenton reaction, inducing cuproptosis. (5) GSH chelates copper ions (Cu⁺), thereby inhibiting the occurrence of cuproptosis. (6) Copper ions (Cu2⁺) induce autophagic degradation of GPX4, further exacerbating ferroptosis. (7) ROS depletes antioxidant defense systems (including GSH and NADPH), further aggravating the occurrence of disulfidptosis. ROS: Reactive oxygen species; NADPH: Nicotinamide Adenine Dinucleotide Phosphate; GPX4: Glutathione peroxidase 4; GSH: Glutathione; System xc⁻: The cystine/glutamate antiporter system (By Figdraw)

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Cuproptosis is a form of cell death triggered by intracellular copper ion overload, primarily mediated through oxidative stress and subsequent cellular damage. Excess copper ions participate in the Fenton reaction, generating large amounts of ROS. These ROS induce lipid peroxidation, protein oxidation, and DNA damage, and ultimately disrupting normal cellular functions [10]. Research on cuproptosis has revealed that copper ions target the acylation of proteins involved in the tricarboxylic acid (TCA) cycle, thus inducing cell death and impairing the function of intracellular enzymes and other proteins. Unlike ferroptosis and disulfidptosis, SLC7A11 does not directly contribute to copper ion accumulation or mitochondrial dysfunction. However, it indirectly influences cuproptosis by maintaining GSH-mediated antioxidant defenses. When the GSH defense system is compromised, ROS clearance becomes inefficient, making cells more vulnerable to copper-induced oxidative damage and accelerating the progression of cuproptosis (Fig. 4).

Both ferroptosis and cuproptosis depend on GSH to maintain redox balance. Additionally, copper can exacerbate ferroptosis by inducing the autophagic degradation of GPX4, which creates a feedback loop between these two pathways. Furthermore, copper-induced ROS also impact both ferroptosis and disulfidptosis, positioning ROS as a central mediator across these cell death pathways. The interplay among these three forms of cell death suggests that they share common regulatory factors and interact within complex cellular networks, particularly under conditions of oxidative stress and metal ion imbalance. This interdependence highlights the therapeutic potential of targeting these pathways. For example, therapies aimed at depleting GSH—commonly employed to target oxidative stress in cancer—can sensitize cells to both ferroptosis and cuproptosis, offering novel treatment strategies. Understanding how these pathways converge through key regulators such as SLC7A11 and GPX4 can aid in the development of more precise and effective therapies, reducing off-target effects and improving efficacy (Fig. 4) [8,9,10, 25]. The relevance of these interactions in cancer treatment is increasingly recognized. For instance, a study demonstrated that the Disulfidptosis-related Ferroptosis (DRF) score, which incorporates genes such as SLC7A11, can predict prognosis and treatment response in hepatocellular carcinoma (HCC). Patients with low DRF scores showed significantly better outcomes, emphasizing the relationship between disulfidptosis and ferroptosis in cancer therapy. These insights provide new strategies for targeting metabolic pathways to address ROS and metal ion imbalances in cancer and other oxidative stress-related diseases [26].

3 Applications of disulfidptosis in digestive tract tumors

3.1 Expression of disulfidptosis-related genes in digestive tract tumors

Recent studies have identified a significant correlation between disulfidptosis-related genes (DRGs) and both the occurrence and prognosis of various digestive tract cancers. The distribution of DRGs with high aberrant expression in digestive tract tumors is detailed in (Table 1). In gastric cancer, genes such as SLC3A2, RPN1, NCKAP1, SLC7A11, PDLIM1, GLA, HIF-1α, VPS35, and CDC37 are overexpressed compared to normal tissues. Conversely, genes like DSTN, FLNA, MYH10, and MYL6 are underexpressed. These genes contribute to tumor proliferation, invasion, and migration [14,15,16,17]. In hepatocellular carcinoma (HCC), DRGs including SLC7A11, INF2, CD2AP, FLNB, ACTN4, CAPZB, ACTB, PDLIM1, FLNA, MYL6, TLN1, and DSTN show high expression levels, whereas ENO1, AGRN, and ZBTB7A exhibit low mutation frequencies. Research by Zhijian Wang’s team has demonstrated that both disulfidptosis-related and glycolysis-related genes are abnormally expressed in HCC, underscoring the critical role of disulfidptosis genes in HCC development [27, 28]. In esophageal cancer, Liu F et al. identified 443 DRGs with abnormal expression. Notably, CD96, CXCL13, IL2RG, LY96, TPK1, and ACAP1 levels are elevated, while SOX17 levels are decreased. These genes are enriched in pathways such as leukocyte adhesion, positive regulation of T cell activation, peptidase activity, and suppression of hydrolase activity [29]. Pancreatic cancer exhibits elevated expression of DRGs including SLC7A11, G6PD, PGD, PRDX1, FLNA, MYH9, TLN1, ACTB, MYH10, SLC3A2, RPN1, NCKAP1, NCKAP1L, WASF2, CYFIP1, ABI2, BAK1, and RAC1 compared to normal tissues [30,31,32]. In colon cancer, Hu G’s team identified 105 genes closely associated with disulfidptosis. Specifically, OXSM is significantly downregulated, while TRIP6, MYH3, and MYH4 are upregulated [33].

Table 1 Distribution of highly abnormally expressed disulfidptosis-related genes in digestive tract tumors
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The abnormal expression of DRGs exhibits significant commonalities across digestive tract tumors. Highly expressed genes such as SLC3A2, RPN1, and SLC7A11 are strongly associated with increased tumor cell proliferation, invasion, and motility. In contrast, genes with low expression levels are frequently linked to reduced cellular structural integrity and weakened adhesion capabilities [14,15,16,17, 27, 28]. These DRGs play critical roles in regulating tumor development, progression, and treatment response by modulating key biological processes, including antioxidant systems, metabolic pathways, cytoskeletal dynamics, and signal transduction.

3.2 Applications of disulfidptosis in the treatment of digestive tract tumors

Disulfidptosis, a novel form of regulated cell death, has recently garnered attention for its potential in treating digestive tract tumors. However, conventional cancer therapies, such as chemotherapy and radiotherapy, are hindered by significant limitations. These treatments lack specificity, often damaging both tumor and healthy cells, leading to severe side effects, including gastrointestinal toxicity, neutropenia, and fatigue. As a result, the doses of these therapies that can be safely administered are restricted, particularly in cancers of the gastrointestinal tract, such as gastric, colorectal, and pancreatic cancers. Additionally, many tumors, including those in the digestive system, develop resistance to chemotherapy, complicating long-term remission and effective treatment. While immunotherapy holds promise, it also faces challenges, with certain cancers—such as hepatocellular carcinoma and colorectal cancer—evading immune surveillance through the expression of checkpoint molecules like PD-L1 and CTLA-4, leading to resistance. Tumor heterogeneity further complicates personalized treatment approaches. In light of these obstacles, disulfidptosis, induced by disulfide bond accumulation and SLC7A11 overexpression, emerges as a promising therapeutic target. This novel cell death mechanism offers the potential to complement existing therapies, reducing the toxicities typically associated with conventional treatments in digestive tract tumors.

3.2.1 Targeting disulfidptosis-related genes: a pathway to precision therapy in digestive tract tumors

The dysregulation of disulfidptosis-related genes (DRGs) and their associated pathways in digestive tract tumors presents promising opportunities for targeted therapeutic strategies. In gastric cancer (GC), Filamin A (FLNA) promotes tumor invasion and migration by degrading matrix metalloproteinase 9 (MMP-9). Additionally, solute carrier family 3 member 2 (SLC3A2) enhances tumor cell proliferation and survival. Ribophorin I (RPN1) and Nck-associated protein 1 (NCKAP1) similarly facilitate tumor invasion and migration through cytoskeletal regulation. In cancers with high SLC7A11 expression, glucose transporter inhibitors such as BAY-876 and KL-11743 effectively block glucose uptake, deplete intracellular NADPH levels, and induce disulfidptosis [16, 34]. Furthermore, Collagen type X alpha 1 chain (Col10A1) drives GC progression by remodeling the extracellular matrix (ECM) and activating the MEK/ERK signaling pathways [35,36,37,38,39]. CD24, a mucin-like membrane glycoprotein, regulates the epidermal growth factor receptor (EGFR) signaling pathway by inhibiting EGFR endocytosis and degradation through a RhoA-dependent mechanism [40, 41]. Neuropilin-1 (NRP1), a transmembrane glycoprotein receptor, plays a pivotal role in tumor angiogenesis and metastasis by interacting with vascular endothelial growth factor (VEGF) and semaphorins. Experimental studies demonstrate that NRP1 knockdown significantly suppresses GC cell proliferation and autophagy, potentially through the modulation of the Wnt/β-catenin signaling pathway and induction of disulfidptosis. Additionally, silencing NRP1 reduces glutamine uptake in GC cells, impairing energy production and biosynthesis. These findings suggest that NRP1 regulates glutamine transporters or metabolic enzymes, highlighting its dual role in angiogenesis and glutamine metabolism. They also underscore its therapeutic potential in GC [42,43,44,45,46]. In colorectal adenocarcinoma (COAD), POU4F1 has been identified as a key oncogenic driver that promotes tumor proliferation and migration through the ERK1/2 and MAPK pathways while enhancing sensitivity to disulfidptosis [47]. Perilipin 4 (PLIN4) regulates mitochondrial β-oxidation, generating ATP and reactive oxygen species (ROS), which may contribute to tissue damage [48,49,50]. In hepatocellular carcinoma (HCC), MYH9 (myosin heavy chain 9) has been shown to overcome sorafenib resistance by promoting disulfidptosis. Inhibition of MYH9 disrupts cytoskeletal integrity, enhances sorafenib uptake, and improves antitumor efficacy, establishing MYH9 as a critical regulator of tumor drug sensitivity [51,52,53,54].

Collectively, these findings underscore the therapeutic potential of DRGs in digestive tract tumors [8, 55]. With further validation through in vitro, in vivo, and clinical trials, key disulfidptosis-related genes could become essential targets for developing targeted therapies for digestive tract tumors.

3.2.2 Disulfidptosis-driven drug sensitivity: advancing therapies for digestive tract cancers

Integrating disulfidptosis-related gene expression patterns with bioinformatics-based drug sensitivity analyses, utilizing IC50 values, has enabled researchers to identify optimal chemotherapeutic agents for specific digestive tract tumors. These findings offer valuable insights for tailoring individualized treatment strategies.

For instance, in gastric cancer (GC), Qian Li et al. identified 89 drugs associated with treatment sensitivity, including Bosutinib and Blebbistatin. Notably, Blebbistatin enhances the efficacy of paclitaxel, while Bosutinib inhibits GC cell migration, highlighting their therapeutic potential [15]. Furthermore, Jie Li et al. demonstrated that high-risk GC patients exhibit resistance to conventional agents such as 5-Fluorouracil, Docetaxel, Erlotinib, Methotrexate, and Paclitaxel [16]. Conversely, Xing Liu et al. reported that low-risk patients respond favorably to agents like Bexarotene, Bicalutamide, Bortezomib, Dasatinib, and Imatinib. Interestingly, high-risk patients show increased sensitivity to Gemcitabine, Gefitinib, Bosutinib, Sorafenib, and Vorinostat [17]. Despite variations in study findings, Bosutinib consistently emerges as a promising therapeutic candidate, warranting further preclinical and clinical validation. In hepatocellular carcinoma (HCC), disulfidptosis-related drug sensitivity analysis revealed that patients with poor prognoses are more sensitive to chemotherapeutic agents such as Gemcitabine, Paclitaxel, and Vinorelbine [28, 56,57,58]. These findings underscore the potential of stratifying patients based on disulfidptosis-related pathways to enhance treatment outcomes. Further exploration of the relationship between disulfidptosis-related gene expression and therapeutic efficacy could optimize HCC management. Additionally, a clinical model of DRG/DRL in HCC identified AC026412.3 as a critical adverse prognostic factor linked to drug resistance and tumor proliferation. Silencing AC026412.3 enhanced the efficacy of gefitinib, highlighting its potential as a promising therapeutic target [59]. In pancreatic adenocarcinoma (PAAD), studies have identified sensitivity to agents such as Bortezomib, Dasatinib, and Cisplatin [30,31,32]. However, these findings are currently limited to preclinical analyses, emphasizing the need for further experimental validation. The potential of disulfidptosis-related pathways to improve therapeutic efficacy in PAAD highlights their importance as a focus for future research. In colorectal cancer (CRC), analyses of disulfidptosis-related ferroptosis genes indicate that high-risk patients are more sensitive to Sorafenib, Pazopanib, and Lapatinib. These findings support the development of personalized chemotherapy regimens for CRC [48]. Additionally, natural compounds such as soy isoflavones and epigallocatechin gallate (EGCG) have demonstrated potential to promote disulfidptosis by targeting glucose transporters (GLUT), reducing glucose uptake, and inhibiting tumor growth [60,61,62,63,64]. These compounds hold promise as adjuvants to existing chemotherapeutic agents.

Disulfidptosis-related pathways provide a robust foundation for advancing personalized therapies across various malignancies. By integrating gene expression profiles with drug sensitivity data, researchers have identified both conventional chemotherapeutics and emerging compounds as potential treatments for digestive tract tumors. Promising candidates such as Bosutinib, Sorafenib, and natural compounds like EGCG exhibit significant therapeutic potential; however, further clinical validation is essential. Future research should focus on refining patient stratification and leveraging disulfidptosis-related pathways to develop innovative and effective cancer therapies tailored to individual patient needs.

3.2.3 Disulfidptosis and immune infiltration: implications for immunotherapy in digestive tract tumors

Immune infiltration plays a critical role in shaping the tumor microenvironment (TME), profoundly influencing tumor progression, therapeutic resistance, and clinical outcomes. Exploring the relationship between immune infiltration and disulfidptosis provides valuable insights for identifying therapeutic targets, predicting patient outcomes, and designing personalized treatment strategies.

Recent studies have highlighted the impact of disulfidptosis on immune cell infiltration and function within the TME. For example, Liao Z et al. demonstrated that high-risk disulfidptosis-related gene (DRG) expression profiles in gastric cancer (GC) are associated with increased infiltration of memory B cells, plasma cells, and activated mast cells. In contrast, low-risk patients exhibited higher levels of γδ T cells, M2 macrophages, and resting mast cells [65]. Additionally, GC patients with high ACTB expression showed greater immune cell infiltration compared to those with low ACTB expression [34]. The expression of NCKAP1 was linked to the presence of M2 macrophages, T helper (Th) cells, central memory T cells (TCM), and dendritic cells (DCs). Moreover, SLC7A11 expression correlated with regulatory T cells (Treg), Th2 cells, and neutrophils. RPN1, SLC3A2, and SLC7A11 were found to positively activate mast cells, while RPN1 and SLC3A2 negatively correlated with memory B cells [14, 16]. In hepatocellular carcinoma (HCC), elevated DRG expression is associated with increased levels of induced regulatory T cells (iTregs), macrophages, natural killer (NK) cells, and T cells, along with a reduction in neutrophil levels. Patients with poor prognosis exhibited heightened infiltration of immune cells such as Tregs, Th1 and Th2 cells, immature dendritic cells (iDCs), neutrophils, M1 macrophages, CD4 + T cells, and plasma cells. Conversely, these patients showed lower levels of CD8 + T cells, naive CD4 + T cells, CD4 + central memory T cells (Tcm), M2 macrophages, and CD8 + effector memory T cells (Tem), along with a decreased CD8 + /Treg ratio. These immune profiles contribute to immunotherapy resistance and unfavorable outcomes. Interestingly, high-risk HCC patients may demonstrate improved responses to immune checkpoint inhibitors (ICIs) because of heightened immune activation within the TME, despite the presence of immunosuppressive mechanisms [58]. Notably, SLC7A11 regulates both glucose and cysteine uptake while modulating immune responses, highlighting its critical role in metabolic adaptation and immune regulation [66]. SLC7A11 shows positive associations with various immune cell types, including Th cells, macrophages, and NK cells, particularly correlating strongly with T helper cells and NK CD56 + cells. The expression of immune checkpoint molecules further illustrates the complexity of immune regulation in HCC. Molecules such as CD40 ligand (CD40LG), CD48, IDO1, CD27, and PDCD1 are highly expressed in patients with better prognoses, whereas CD276 expression is elevated in those with poor outcomes. These findings suggest that immune checkpoints play a critical role in tumor progression and may serve as promising therapeutic targets, particularly in low-risk populations [27, 28, 56,57,58, 67, 68]. In pancreatic adenocarcinoma (PAAD), Li et al. found that disulfidptosis influences immune infiltration, as Tr1 cells positively correlating with DRG expression and neutrophils showing an inverse correlation. Five key DRGs—S100A4, SLC7A11, PRDX1, SLC7A7, and DIAPH3—have been identified as potential regulators of the TME, impacting Th2 cells, macrophages, and plasmacytoid dendritic cells (pDCs). These findings underscore the potential of targeting DRGs to reprogram the TME [31]. Similarly, Yang et al. demonstrated in colorectal cancer (CRC) that tumor-associated macrophages (TAMs) and myeloid-derived suppressor cells (MDSCs) are enriched in high-risk disulfidptosis subtypes. These cells foster an immunosuppressive TME by secreting cytokines and activating immune checkpoints, thus suppressing T cell responses and facilitating tumor progression [69].

Immune checkpoint inhibitors (ICIs) targeting PD-1, PD-L1, and CTLA-4 have revolutionized cancer treatment. In disulfidptosis-associated subtypes, high expression of PD-L1 and CTLA-4 correlates with poor prognosis but also indicates that disulfidptosis may induce immunogenic cell death (ICD), converting “cold” tumors into “hot” tumors that are more responsive to ICIs. Furthermore, the elevated expression of HLA family genes in high-risk subtypes reinforces their potential as biomarkers for predicting immunotherapy responses. The dual role of disulfidptosis in regulating tumor metabolism and immune responses establishes DRGs as promising targets for precision immunotherapy. Combining ICIs targeting PD-L1, PD-1, or CTLA-4 with therapies aimed at DRG-mediated pathways, such as SLC7A11 inhibition, may enhance immune activation and overcome resistance [66]. By systematically analyzing the relationship between immune infiltration and disulfidptosis in digestive tract tumors, researchers can gain a deeper understanding of the dynamic changes within the TME. This knowledge can guide the development of more precise and effective immunotherapies, ultimately improving patient outcomes and extending survival rates.

3.3 Applications of disulfidptosis in prognosis of digestive tract tumors

Disulfidptosis, a recently identified form of regulated cell death driven by the accumulation of disulfide bonds under stress conditions, has emerged as a promising prognostic factor in digestive tract cancers. Studies have demonstrated that the expression profiles of disulfidptosis-related genes (DRGs) are closely associated with clinical outcomes. For instance, in gastric cancer (GC), high expression levels of GLA, CDC37, VAMP7, ALG1, and ANKZF1 are linked to favorable prognosis. In contrast, elevated levels of CD24, MAGE-A3, SERPINE1, IRGM, NRP1, HIF-1α, VPS35, PLS3, GRP, APOD, SGCE, COL8A1, NCKAP1, VCAN, NT5E, and SLC7A11 are associated with poor prognosis and advanced clinical stages [14,15,16, 40, 65]. In hepatocellular carcinoma (HCC), DRG expression exhibits significant prognostic variability. High expression levels of CBR4, SEC31B, SPP2, RDH16, LCAT, TRIM55, GHR, OGN, TCP10L, and DNASE1L3 are associated with improved prognosis. Conversely, elevated levels of GNL2, NDRG1, TMCO3, TRIB3, SLC7A11, LRPPRC, CDCA8, GAGE1, PPP2R2C, TNFRSF11B, IL8, TREM1, SLC2A1, SCIN, AKR1B15, MMP1, CORIN, SLC1A5, GAGE4, and NEIL3 correlate with poor outcomes (Table 2) [27, 56, 57, 67, 68]. Similarly, in colorectal adenocarcinoma (COAD), POU4F1 has been identified as a critical prognostic marker, with its overexpression significantly correlating with reduced survival rates [47].

Table 2 Correlation between the expression of genes related to disulfidptosis and prognosis in digestive tract tumors
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These findings highlight the potential of integrating DRG expression profiles with clinical tools to establish a robust framework for individualized cancer prognosis and treatment strategies. Key biomarkers such as SLC7A11, POU4F1, CD24, and NRP1 show considerable promise in enhancing prognostic accuracy and guiding targeted therapies. Compared to single-gene analyses, risk scores that incorporate multiple DRGs demonstrate superior predictive capability, providing more comprehensive insights for clinical evaluation. Furthermore, combining these risk scores with clinical features, laboratory findings, and imaging data could facilitate the development of multidimensional prognostic models. Such approaches have the potential to enable precise and personalized cancer therapies, thereby advancing the broader field of oncology.

4 Conclusions and future perspectives

In conclusion, disulfidptosis, a recently identified form of regulated cell death, plays a crucial role in the development and treatment of digestive tract tumors. This review underscores the therapeutic and prognostic potential of disulfidptosis, particularly through key genes such as SLC7A11, SLC3A2, NCKAP1, and NRP1, which serve as significant biomarkers and therapeutic targets. These genes influence tumor progression, immune modulation, and therapeutic resistance, providing novel insights into treatment strategies. The unique focus of this review is on emphasizing disulfidptosis’ role in overcoming chemoresistance and enhancing immunotherapy efficacy, offering new therapeutic avenues for treating difficult-to-target cancers.

Future research should give priority to validating the functional roles of these genes in various models and conducting large-scale clinical trials to confirm their predictive value as biomarkers for patient stratification and treatment response. Further studies into the interactions between disulfidptosis and other cell death pathways, such as ferroptosis and cuproptosis, will deepen our understanding of their collective impact on tumor progression and therapy. This exploration is crucial for developing combination therapies that optimize the benefits of each mechanism.

Additionally, identifying additional regulators of disulfidptosis and exploring its molecular pathways may lead to new therapeutic strategies. For instance, small molecule inhibitors targeting oxidative stress pathways or disulfide bond formation could not only induce disulfidptosis but also sensitize cancer cells to conventional therapies. Combining disulfidptosis induction with chemotherapy or immunotherapy has the potential to improve treatment outcomes, particularly in drug-resistant tumors. Investigating the role of immune checkpoint inhibitors in modulating disulfidptosis may provide new opportunities for combination immunotherapies.

In summary, advancing disulfidptosis research through interdisciplinary collaboration and technological innovation is essential for developing more precise diagnostic tools and therapeutic approaches. By exploring the complex relationships between disulfidptosis, immune infiltration, and tumor progression, we can enable the development of personalized treatment strategies, improving patient outcomes and the quality of life for individuals with digestive tract cancers.