The invasive and metastatic potential of CRC is associated with poor prognosis, and members of the KLF family display complex biological functions in the regulation of the TME. Studies have been conducted to study the functional mechanisms of several KLF family members and their clinical relevance in CRC (Table I). In CRC tissues and cell lines, the expression levels of KLF1, KLF5, KLF8 and KLF12 are relatively high, while the expression levels of KLF3, KLF4, KLF13 and KLF14 are expressed at lower levels. These highly expressed members generally act as tumor-promoting factors.

Shen et al (53) reported that KLF3 regulates the behavior of CRC cells by the Wnt/β-catenin signaling pathway. WNT1 is a direct downstream target of KLF3, and its regulation promotes malignant phenotypes in CRC cells. In addition, decreased KLF3 expression increases CRC cell proliferation, migration and invasion, with the miR-365a-3p axis being instrumental in the regulation of migration, invasion and chemoresistance (54). Low levels of KLF4 favor CRC cell proliferation, invasion and epithelial-mesenchymal transition (EMT) (55). Mechanistically, KLF4 is a direct target of miR-29a. Clinical studies have demonstrated that upregulated miR-29a directly targets KLF4, modulating the MMP2/E-cadherin signaling axis and promoting CRC metastasis (56,57). Similarly, miR-92a can increase CRC cell proliferation and migration by regulating KLF4 and its downstream effector p21 (58). The TF KLF5 is a downstream target of the MAPK-ERK-RAS pathway and is regulated by early growth response factor 1 (EGR1). KRAS activation plays an important role in the pathophysiology of CRC, and KLF5 expression is required for the oncogenic and proliferative effects of KRAS, making it a pathogenic factor in CRC (29,59,60). The tumor suppressor APC, a key gene involved in the pathogenesis of CRC (61), controls the activity of Wnt signaling pathway via regulation of the activity of β-catenin. KLF5 is an important mediator of these interactions, and its absence can prevent the oncogenic effects of APC mutations and activation of the Wnt signaling pathway, providing further support for its oncogenic role in CRC (59,62). Additionally, KLF12 is involved in tumor growth through direct activation of EGR1 (63).

Conversely, some of the KLF family members are tumor suppressors in CRC. KLF2 is relatively highly expressed and KLF6, KLF7, KLF9 and KLF17 are expressed at lower levels. Overexpression of KLF2 suppresses the invasion, migration, EMT and xenograft tumor growth of CRC cells. Mechanistically, KLF2 causes ferroptosis by inhibiting the PI3K/AKT pathway (64) and controls the behavior of CRC cells through the hypoxia inducible factor-1α/Notch-1 signaling pathway as a tumor suppressor (65). Another tumor suppressor, KLF6, may be involved early in tumorigenesis (66,67). Downregulation of KLF6 splice variant KLF6-SV2 is associated with the progression of CRC. KLF6-SV2 upregulates p21 and Bax thus leading to cell cycle arrest, inhibition of cell proliferation and induction of apoptosis (68). Finally, KLF17 inhibits CRC cell adhesion, invasion and EMT, and is a tumor suppressor as well as a potential independent prognostic biomarker for patients with CRC (12).

Although the bidirectional regulatory network of the KLF family in CRC has been unveiled by current research, the complexity of these interactions remains a major challenge. It is important to note that the majority of existing studies are based on in vitro cell lines and xenograft models (17,18), which fail to capture the heterogeneity and complexity of the human TME. The development of targeted molecules, such as inhibitors of KLF5 or activators of KLF6, shows promise but their efficacy and safety need to be validated in models that more closely reflect the clinical setting. In addition, the complex cross-regulatory network between KLF family members is not fully understood. For example, whether KLF3 and KLF5 are synergistic or antagonistic in the Wnt signaling pathway and how such cross-regulation affect tumor cell responses to targeted therapies are not known. Addressing these questions will be important for improving the understanding of KLF-mediated mechanisms in CRC and for the development of effective therapeutic strategies in future studies.

The aggressive biological behaviors of GC, including invasion, metastasis and chemoresistance, are associated with poor patient prognosis. The KLF family plays a key role in the development of GC, and also in the regulation of the TME. Studies show that in GC patient tissues and cell lines, KLF3, KLF5, KLF11 and KLF16 are at relatively high expression levels while KLF2, KLF4, KLF9 and KLF15 are relatively low in expression. Collectively, these members of the KLF family are tumor-promoting factors in GC (Table II).

Wang et al (69) reported that KLF2 is expressed at low levels in gastric tumors and its downregulation is associated with poor survival of patients with primary GC. Diminished expression of KLF2 is involved in the acquisition of malignant phenotypes in GC cells. Beyond mechanistic insights, a registered clinical study at Nanfang Hospital, Southern Medical University (Guangzhou, China) (ChiCTR1900027330), further explored the clinical relevance of KLF2 in cancer. This observational study, based on human tissue samples, discussed the regulation of cancer cell invasion and metastasis mediated by the TF FOXK1 through CTGF and KLF2. Registered in November 2019, the research highlights the clinical importance of KLF2 in tumorigenesis and ongoing efforts to bring basic findings to clinical practice. Subsequently, Li et al (70) found that KLF3 is highly expressed in GC tissues. Overexpression of KLF3 facilitates GC cell proliferation, migration, invasion and EMT. Mechanistically, the WNT1 promoter is activated by direct binding of KLF3, which results in nuclear accumulation of β-catenin and activation of the Wnt/β-catenin signaling pathway. Inhibition of WNT1 reverses the malignant phenotype induced by KLF3 (53), and in vivo experiments confirm that KLF3 promotes tumor growth and metastasis.

Helicobacter pylori (Hp) is a known carcinogenic agent for GC. KLF4 is frequently a tumor suppressor in GI tumors. Studies have shown that Hp promotes the development of GC by inhibiting the expression of KLF4 (71–73). Knockdown of KLF4 promotes GC cell proliferation, migration and invasion by modulating E-cadherin and modulating the Wnt/β-catenin signaling pathway, thus promoting EMT (74,75). Mechanistically, miR-135b-5p has oncogenic effects in GC cells by reducing KLF4 (76). KLF5 is upregulated in GC tissues, and its high expression is associated with poor patient prognosis. Functional studies suggest that KLF5 knockdown diminishes the proliferation of GC cells and induces cell cycle arrest at the G₀/G₁ phase. This effect is mediated, at least in part, through the regulation of cell cycle-related proteins, including p21 and CDK4, and thus KLF5 controls GC cell proliferation (77,78) (Fig. 1). Ji et al (79) found that KLF11 facilitates GC invasion and migration through its overexpression of Twist1. In a clinical study, KLF15 was found to improve GC cell proliferation through the downregulation of CDKN1A/p21 and CDKN1C/p57, and its expression levels may be a prognostic indicator for patients with GC (80). KLF16 is highly expressed in GC tissues. Knockdown of KLF16 suppresses GC cell proliferation by upregulating p21 expression and downregulating CDK4 levels, thus suggesting that KLF16 promotes cell proliferation by modulating these cell cycle regulators (81). Furthermore, high KLF16 expression plays a role in GC growth and metastasis by modulating the Notch signaling pathway (82).

However, there are members of the KLF family that serve as tumor suppressors in GC. In patient tissues and cell lines, KLF7, KLF10, KLF12 and KLF13 are relatively highly expressed while KLF1 and KLF6 have lower expression levels. Li et al (83) showed that silencing KLF1 inhibits the proliferation of GC cells, which was associated with decreased cell viability, decreased DNA synthesis, and G₁ phase cell cycle arrest, resulting in a lower percentage of cells in the S phase. KLF1 knockdown also inhibits activation of the Wnt/β-catenin pathway, which inhibits GC cell migration, invasion and the EMT process (83). Studies have shown that microRNAs (miRNAs) can regulate GC malignancy through KLF12. Specifically, miR-138-5p inhibits GC cell invasiveness by direct targeting of KLF12 (84), and overexpression of miR-200a-3p inhibits GC cell proliferation and cell cycle progression and migration by targeting KLF12, with tumor-suppressive effects (85). These results highlight the central role of KLF12 as a downstream effector of miRNAs in the regulation of GC malignancy. KLF13 has been reported to suppress GC cell proliferation, possibly by autophagic degradation of the Wnt signaling pathway protein, β-catenin, leading to decreased expression of β-catenin and downstream molecules Cyclin D1 and MYC. This mechanism causes the cell cycle to arrest at the G2/M phase (86). Contrarily, other studies indicate that KLF13 facilitates GC cell migration and invasion by activating the NF-κB/EMT signaling axis (87,88). These seemingly contradictory results are likely to reflect the influence of cellular context: The balance between proliferation and migration programs may be dependent on the particular repertoire of interacting proteins, post-translational modifications or microenvironmental cues that are present in different experimental systems or tumor subtypes. The context-dependent behavior of KLF13 underscores the complexity of the function of KLF family members in GC.

In summary, the KLF family has a key regulatory role in the tumorigenesis, progression and TME modulation of GC. By activating canonical signaling pathways, such as Wnt/β-catenin, KLFs affect malignant phenotypes including cell proliferation, invasion, metastasis and chemoresistance, all of which are associated with poor patient prognosis. Despite these insights, clinical translation is still difficult. For example, although KLF12 is a key regulator of GC malignancy as a downstream target of multiple miRNAs, studies are largely correlative and lack direct evidence that targeting KLF12 itself (26), and not its upstream miRNAs, can provide therapeutic benefit. Additionally, the functional role of KLF13 in GC is still controversial because the same molecule may exert opposite effects depending on the cellular context or experimental conditions. These observations indicate the necessity of caution in interpreting available data and the importance of systematic approaches, such as functional analyses at the single-cell level, to elucidate the specific biological roles of KLF family members in GC.

In HCC, several members of the KLF family have been widely studied. Studies have shown that in tissues from patients with HCC and cell lines, KLF5, KLF7, KLF8, KLF13 and KLF15 are abundantly expressed, while KLF3, KLF6, KLF9 and KLF17 are low expressed. Collectively, these members of the KLF family are tumor-promoting factors in HCC (Table III).

In HCC, KLF3 has been found to be a direct target of miR-660-5p. Functional studies show that miR-660-5p enhances HCC cell proliferation, colony formation and invasive and migratory abilities by inhibiting KLF3 expression. It also inhibits apoptosis and induces EMT phenotype (89–91). KLF5 is an oncogene in HCC, and it drives cell proliferation, and tumor proliferation and metastasis (92). Mechanistically, KLF5 is responsible for inducing EMT by activating the PI3K/AKT/Snail pathway. In a set of HCC cell lines, the silencing of KLF5 leads to a notable decrease of mesenchymal markers, such as N-cadherin and vimentin, as well as the TF Snail, and an increase in the epithelial marker E-cadherin (93). These results indicate that the targeting of KLF5 may be a potential therapeutic approach for HCC. KLF7 has also been found to be an oncogenic factor in HCC, with its abnormal expression being associated with malignant progression (94). Tryptophan metabolism is a central regulatory node within the TME and is important in HCC proliferation, metastasis and invasion. KLF7 transcriptionally regulates an amino acid transporter SLC1A5, which forms the KLF7/SLC1A5 axis, promoting the uptake of tryptophan and metabolic reprogramming to maintain the malignant phenotype of HCC cells (95). These results suggest that the KLF7/SLC1A5 axis may provide a molecular target for the treatment of HCC and is a novel strategy to intervene in aberrant tryptophan metabolism. KLF8 overexpression activates Wnt/β-catenin signaling pathway target genes, such as c-Myc, Cyclin D1 and Axin1 (96). Functional studies have shown that KLF8 upregulation has a notable effect on HCC cell proliferation and invasion, inhibits apoptosis and induces EMT through modulation of the expression of epithelial and mesenchymal markers, downregulating N-cadherin, vimentin and fibronectin and upregulating E-cadherin (13,97). Clinical correlation analysis suggests that high expression of KLF8 may be a molecular marker of poor prognosis or early recurrence in surgical patients with HCC (13). Additionally, KLF9 inhibits the proliferation of HCC cells and positively regulates p53 expression (98) while low expression of KLF17 is notably associated with increased tumor invasiveness and poor patient prognosis (99). Mechanistically, KLF17 inhibits tumor growth and metastasis by regulation of the TGF-β/Smad signaling pathway (100).

Further research has shown that some members of the KLF family are tumor suppressors in HCC. In tissues from patients with HCC and cell lines, KLF6 and KLF14 are relatively highly expressed, while KLF2 and KLF4 are expressed at lower levels. Notably, KLF2 is downregulated in HCC samples, and its overexpression inhibits the growth, migration and colony-forming ability of liver cancer cells (101). Mechanistically, KLF2 exerts its tumor-suppressive effects by means of a negative feedback loop in the TGF-β/Smad signaling pathway (102). However, the long non-coding RNA, FBXL19-AS1 is upregulated in HCC and interacts with KLF2 to promote tumor cell proliferation, cell cycle progression and prevent apoptosis, thus worsening HCC progression (103). KLF4 is also a tumor suppressor in HCC with multiple regulatory functions. It reverses EMT by inhibiting the TFs Slug (104) and notably inhibits HCC cell proliferation and migration by upregulating cadherin 3 and activating the GSK-3β signaling pathway (105). Additionally, KLF4 is a major transcriptional regulator of monoglyceride lipase (MGLL), with the KLF4-MGLL axis being central to inhibiting HCC cell migration (106). In terms of metabolic regulation, KLF4 acts as a target of miR-206 and its downstream effector RICTOR, inhibiting the progression of HCC by decreasing tumor cell ATP synthesis (35). Notably, the deubiquitinase DUB3 forms a positive feedback loop with KLF4 to maintain KLF4 protein stability and cooperatively suppress HCC tumor growth and chemoresistance (107). Collectively, these mechanisms point to the tumor-suppressive activity of KLF4 and suggest that the activation of the DUB3/KLF4 pathway may be a potential therapeutic strategy against HCC progression. The expression and biological roles of KLF6 in HCC have also attracted much attention. Inhibition of KLF6 notably impairs cell proliferation and causes G₁-phase cell-cycle arrest, mainly by inhibition of the expression of CDK4 and cyclin D1, which results in the inhibition of retinoblastoma protein phosphorylation (108,109). KLF6 silencing also results in further upregulation of the tumor suppressor p53 and downregulation of the anti-apoptotic protein, Bcl-xL, leading to apoptosis (110). These findings suggest a key role of KLF6 in the control of cell cycle progression and apoptosis in HCC cells. Additionally, KLF6 has tumor suppressor properties, including the inhibition of the PI3K/AKT signaling pathway, which increases the sensitivity of liver cancer cells to chemotherapeutic agents. Promoter methylation of KLF6 leads to loss of expression, which is highly related to the progression of HCC. Restoration/enhancement of KLF6 expression thus represents an attractive therapeutic avenue for suppressing the malignant progression of liver cancer (111–113) (Fig. 2A).

In summary, the KLF family is involved in the development of HCC through a complex regulatory network. The double biological roles of its members, along with the interaction between metabolic reprogramming and signaling pathways, provide new insights for clinical intervention approaches. Elucidation of molecular mechanisms of KLF family members in HCC is of great scientific importance for identification of potential therapeutic targets and combination strategies targeting the KLF signaling axis. Such studies have offered an innovative theoretical basis and translational framework for the accurate diagnosis, treatment and prognosis of HCC.

Being an aggressive GI malignancy, EC is associated with highly invasive and metastatic potentials, which are associated with low prognosis. The systematic study of the KLF family in EC, however, is not very extensive. KLF5 is typically highly expressed in patient tissues and cell lines, but at a relatively low level in KLF12 and KLF17. These relatives play the role of tumor-promoting factors in EC (Table IV).

KLF5 is abnormally overexpressed in esophageal squamous cell carcinoma (ESCC), and the level of its expression is positively associated with the status of tumor differentiation and lymph node metastasis (114). Functional research has shown that KLF5 facilitates ESCC cell proliferation, migration and invasion, making it a primary contributor to tumor malignancy (115). KLF5 is an oncogenic signaling cascade that transcriptionally activates fibroblast growth factor-binding protein 1 and Snail family transcriptional repressor 2, and cooperatively controls extracellular matrix remodeling and the EMT process, in a mechanistic manner (115). The regulation of JNK signaling pathway by KLF5 has two effects: i) KLF5 activates the apoptotic pathway of BAX by stimulating the activation of the JNK pathway by apoptotic upstream regulators, apoptosis signal-regulating kinase 1 and mitogen-activated protein kinase 4; ii) KLF5-mediated excessive malignant proliferation is counter-regulated by JNK pathway activation; and, KLF5-mediated apoptosis is reversed by JNK inhibition and cell survival is restored (116). This mechanism shows that KLF5 actively regulates the JNK pathway to ensure TME homeostasis to balance oncogenic and pro-apoptotic activities (Fig. 3B).

Recently, it has been demonstrated that sustained suppression of KLF5 is capable of triggering an EMT phenotype without depending on the β-catenin and TGF-β signaling pathways (29,117,118). The ubiquitin proteasome system-targeted small-molecule inhibitor ML264 induces KLF5 degradation, leading to re-establishment of the epithelial cell transcriptional program and a massive increase in cell migration and invasion potential (118). The phenomenon does not only demonstrate a non-canonical regulatory process of KLF5 in ESCC-related EMT but it also gives a new understanding of cellular plasticity regulation in normal esophageal tissue repair. KLF5 translational research in EC is developing towards clinical practice. The mechanistic role of the KLF5/USP37/ programmed cell death ligand 1 (PD-L1) signaling axis in facilitating ESCC progression and immune evasion is the subject of a recently registered clinical study (119) at the First Affiliated Hospital of Baotou Medical College, Inner Mongolia University of Science and Technology (Baotou, Inner Mongolia Autonomous Region, China) (ChiCTR2500106315), which was registered in July 2025. This human tissue-based observational study is an important step in confirming the preclinical results of KLF5-mediated immune regulation and can be the basis of developing KLF5-targeted immunotherapies in the treatment of EC. According to Zhang et al (120), the downregulation of KLF12 enhances cisplatin resistance and metastasis in ESCC. KLF12, in a mechanistic manner, can bind to the promoter of the L1 cell adhesion molecule (L1CAM) to silence its expression, and L1CAM silencing can reverse the cisplatin-resistant and metastatic phenotype caused by KLF12 deficiency (121). Subsequent research showed that E3 ubiquitin ligase TRIM27 interacts with the N-terminal region of KLF12 and causes ubiquitination of KLF12 to block the transcriptional activity of KLF12. TRIM27 depletion increases the repression of L1CAM by KLF12, which reverses tumor cell drug resistance and metastatic potential (122). Taken together, these results indicate the fundamental regulatory importance of the KLF12/TRIM27/L1CAM signaling axis in cisplatin resistance and metastasis in ESCC. Also, a clinical study (123) indicated that KLF17 is lowly expressed in EC tissues and its inhibition increases the proliferative, migratory and invasive abilities of EC cells.

Despite the fact that the role of the KLF family in EC has not been widely studied, some of its members have been established to have tumor-suppressive roles in disease progression. The role of KLF4 in EC is controversial. The expression of KLF4 in ESCC is stage-specific and is associated with patient prognosis and tumor invasiveness (42). KLF4 acts as a tumor suppressor during the initial phases of the ESCC and downregulation of this gene triggers tumorigenesis by increasing unregulated cell proliferation and disrupting DNA repair (42,43). Conversely, during the late tumor progression, when the accumulation of mutations in the key oncogenes and tumor suppressor genes occurs, KLF4 can be re-expressed abnormally or its activity can be hijacked, thus facilitating tumor invasion and metastasis (38,124). This functional switching depends on the stage, which is similar to other TFs, including TGF-β, which is tumor-suppressive at early stages but pro-metastatic at late stages (38,125) (Fig. 3A).

KLF4 also has a strong interaction with the cellular microenvironment and its interacting partners. KLF4 stimulates p21-mediated cell cycle arrest and DNA repair in early-stage ESCC cells with an intact p53 signaling pathway, which supports its tumor-suppressive effect (43). Conversely, in late-stage cells where key signaling nodes are perturbed, for example, p53, KLF4 can be involved in transcriptional programs that facilitate cell survival, migration and invasion. Moreover, the activation of cofactors, post-translational modifications (for example phosphorylation and acetylation) and cross-talk with other signaling pathways (for example Wnt/β-catenin, Notch and NF-κB) can considerably modify the transcriptional output of KLF4 (42).

KLF4 regulatory mechanisms are dynamic and vary with the disease progression. Promoter hypermethylation or certain microRNAs (for example, miR-29a, miR-92a or miR-135b-5p) can repress KLF4 expression in the early-stage ESCC, leading to the loss of its tumor-suppressive activity (56,58,76). In advanced tumors, KLF4 re-expression can be stimulated by inflammatory signals or activation of oncogenic pathways in the TME through other mechanisms. KLF4 can also be modified by tumor-associated kinases or ubiquitin ligases which can change its transcriptional activity and its specificity to target genes. Such contextual plasticity is essential in designing effective targeted therapies: In early ESCC, KLF4 agonists can potentially re-establish tumor-suppressive activity, but in advanced tumors, the same strategy can potentially stimulate disease progression. Thus, the focus of future clinical trials must be on the stage-specific approaches and strict patient stratification.

In conclusion, the seemingly conflicting role of KLF4 in ESCC can be attributed to the fact that it was a tumor suppressor in early phases but a potential oncogenic driver in late phases, which depends on the tumor stage, cellular context and dynamic interactions with upstream regulatory networks. The knowledge of these context-dependent processes is key to explain discrepant results and inform KLF4-targeted therapy based on disease stage and molecular phenotypes.

KLF9 is also highly repressed in ESCC and acts as a tumor suppressor. It suppresses cell growth, migration and invasion of ESCC cells. KLF9, in its mechanistic interaction with TF4, inhibits the β-catenin/TF signaling pathway and silences target genes including Cyr61 (126,127). In general, ESCC is a violent GI neoplasm, and the metastatic nature is associated with poor prognosis. Even though the investigation of the KLF family in ESCC is comparatively new, the studies (128,129) have shown a dual regulatory effect of particular family members in the initiation and progression of tumors, which provides new insights into the mechanisms of its development and the possible treatment options. A comprehensive study of KLF expression patterns and functional regulatory networks may help shed light on the molecular mechanism of ESCC invasion and metastasis, which is important as a key theoretical basis to enhance patient survival, quality of life and overcome drug resistance. Further research efforts are needed on multi-target combination therapies and interventions targeting EMT pathways and metabolic reprogramming to increase tumor cell susceptibility to chemotherapy. In conclusion, a deeper understanding of the molecular processes of members of the KLF family will present a more exhaustive basis for accurate diagnosis and treatment of ESCC and will lead to the creation of individual therapeutic approaches.

As one of the most malignant tumors in the digestive tract (1), PC has increasingly become a research focus for the study of the regulatory mechanism of KLF family. In PC tissues and cell lines, KLF5, KLF7, KLF8 and KLF16 are relatively highly expressed whereas KLF9 and KLF10 are expressed at lower levels. The majority of these KLF members are tumor promoters in PC (Table V).

In patient tissues, KLF5 is highly expressed and expression levels are notably associated with prognosis. Mechanistic studies indicate that KLF5 transcriptionally activates E2F1, Cyclin D1 and Rad51 and represses p16 to drive the cell cycle from G₁ to S phase and promote tumor cell proliferation (130–132). A study in 2025 identified KLF5 as a transcriptional regulator of miR-1305 which inhibits the proliferation of PC cells and induces apoptosis through the KLF5-ERBB2 signaling axis, offering a promising diagnostic and therapeutic target (133). In pancreatic ductal adenocarcinoma (PDAC), KLF7 is overexpressed, and its dysregulation has an important role in promoting tumor cell proliferation and metastatic potential. Mechanistically, KLF7 is responsible for the activation of interferon-stimulated gene transcription programs as well as the maintenance of the structural integrity of the Golgi apparatus, which may carry out a role in therapeutic resistance associated with tumor growth and metastasis (134,135).

KLF8 is also overexpressed in PC tissues and cells. Functional studies have shown that KLF8 knockdown markedly blocks cell proliferation and tumor formation and induces G2/M phase cell cycle arrest. Mechanistically, KLF8 depletion causes a downregulation of CDK1/CDC2, Cyclin B1 and Cyclin D1 and an upregulation of the cell cycle inhibitors p21 and p27 (136). KLF8 is a major inducer of EMT and tumor invasiveness, and its expression levels are associated with overall survival (OS) and is an independent prognostic predictor (137,138). By contrast, KLF9 is lowly expressed in PC tissues. Clinicopathological analyses have found that low KLF9 expression is associated with poor tumor differentiation, deep vascular invasion and low OS (139). Mechanistically, KLF9 negatively regulates the Wnt/β-catenin pathway by suppressing the expression of mRNA and protein at the promoter of Frizzled-5, which suppresses PDAC tumor development (140). Overexpression of KLF9 downregulates MMP-2, MMP-9, Bcl-2 and markers of mesenchyme (N-catenin) while upregulating markers of epithelium (E-catenin), pro-apoptotic proteins (Bax, p53) and cell cycle regulators (CDK4, Cyclin D1), collectively inhibiting tumor invasion and metastasis and regulating proliferation (141).

Although the oncogenic functions of members of the KLF family in PC are well known, recent studies suggest that some members may have tumor-suppressive functions under certain microenvironments or molecular contexts (9,142).

Clinical studies have demonstrated that KLF2 is overexpressed in PDAC samples and its overexpression prevents the growth, migration metastasis of PC cells (143,144). Mechanistically, KLF2 interacts with β-catenin and negatively regulates the β-catenin/TF signaling pathway (145). Further studies suggest that KLF2 knockdown affects cellular senescence and decreases p21 expression (146). KLF3 is a direct downstream target of miR-324-5p, which leads to a decrease in KLF3 expression. In PC tissues and cell lines, miR-324-5p is notably upregulated, and inhibition of this microRNA inhibits cell proliferation and induces apoptosis (147). Additionally, exosomal miR-21-5p from M2 macrophages negatively regulates KLF3 in PC stem cells and boosts tumor proliferation (148). KLF4 shows context-dependent function in pancreatic cancer. Knockdown of KLF4 triggers EMT, which greatly enhances the proliferative and metastatic potential of tumor cells. Mechanistic studies have shown that KLF4 downregulation causes an upregulation of Cav-1 and vimentin and a downregulation of E-cadherin (149,150). Conversely, KLF4 can inhibit tumor growth and metastasis by activating the p27 pathway (151), as well as by directly downregulating CD44, limiting metastatic spread (152). These findings support the development of KLF4-based targeted therapeutic strategies for advanced pancreatic cancer. KLF6 overexpression also suppresses proliferation, metastasis and EMT progression in PC cells, suppressing tumor progression through the upregulation of activating transcription factor 3 (153).

In summary, PC is an aggressive GI cancer, and the regulatory mechanism of KLF family members has attracted much research attention. KLFs have dual and context-dependent roles in pancreatic cancer, which are dependent on molecular, cellular and microenvironmental factors. An improved understanding of their mechanisms will lead to improved understanding of the pathogenesis of PC and the discovery of new targets for precision diagnostics and therapeutics, which may improve the prognosis of patients.

Future studies should be aimed at understanding the specific functions of individual KLF members in different microenvironments, their interactions and the influence of epigenetic modifications, such as methylation of the promoter, on their expression. Such studies will provide the basis for precision medicine approaches in pancreatic cancer.