MNAT1 in gastrointestinal cancers: mechanistic insights and therapeutic strategies—a narrative review

Introduction

Gastrointestinal (GI) cancers account for more than one-fourth of global cancer incidence and approximately one-third of cancer-related deaths (1). This group includes colorectal, gastric, liver, pancreatic, oesophageal, and gallbladder cancers and represents a major public-health burden. Despite advances in surgery, chemotherapy, radiotherapy, and targeted therapies, outcomes remain poor for many patients. A clearer understanding of the molecular mechanisms underlying GI tumorigenesis is therefore essential for identifying new therapeutic targets and improving early detection.

Ménage à trois 1 (MNAT1) is a core subunit of the cyclin-dependent kinase (CDK)-activating kinase (CAK) complex and regulates both cell proliferation and transcription (2). Accumulating evidence indicates that MNAT1 is dysregulated in multiple cancers and is associated with disease progression (3,4). For example, elevated CDK7, cyclin H, and MNAT1 expression correlate with poor prognosis in oestrogen receptor-positive breast cancer, suggesting potential prognostic value (4). In osteosarcoma—one of the most common aggressive bone cancers in adolescents and young adults—MNAT1 silencing suppresses proliferation and invasion and reduces tumour growth (3). Several studies also suggest an association between MNAT1 and colorectal cancer prognosis (5,6). In this review, we summarize MNAT1’s roles in cell-cycle control and transcriptional regulation and discuss its potential as a therapeutic target in GI cancers. We present this article in accordance with the Narrative Review reporting checklist (available at https://jgo.amegroups.com/article/view/10.21037/jgo-2026-1-0186/rc).

Methods

The following search strategy was employed to focus on MNAT1, GI cancer, CAK complex, and therapeutic targeting (Table 1). We conducted a literature search in relevant databases, including PubMed and Web of Science. We limited our selection to original research articles, systematic reviews, meta-analyses, and key narrative reviews. The search timeframe spanned from the earliest relevant records to the present [2026], with a focus on recent advancements. Articles without full available text, meeting abstracts, and non-English publications were excluded.

The roles of MNAT1 in cancer pathogenesis

Emerging evidence supports a central role for MNAT1 in core cellular programs relevant to tumorigenesis. MNAT1 is a highly conserved mammalian gene encoding a zinc-finger protein (309 amino acids) that functions as a core subunit of the CAK complex. CAK comprises CDK7, cyclin H, and MNAT1 and regulates both the cell cycle and transcription (2). MNAT1 promotes cell-cycle progression by facilitating CAK-mediated activation of CDKs (CDK1/2/4/6), including regulation of the G1/S transition. In addition, MNAT1 supports transcription initiation through integration of CAK into the transcription factor II H (TFIIH) complex and phosphorylation of the C-terminal domain (CTD) of polymerase II (Pol II), and it contributes to DNA repair via transcription-coupled nucleotide excision repair (TC-NER) (7-9).

Cancer is a multifactorial disease driven by genetic, epigenetic, metabolic, and microenvironmental perturbations, characterized by uncontrolled proliferation, metastatic potential, and evasion of homeostatic constraints. Key contributors include oncogene activation and tumour-suppressor loss, epigenetic dysregulation (e.g., altered DNA methylation and chromatin remodelling), metabolic reprogramming (e.g., the Warburg effect), and immune–microenvironment interactions. Viral infections and lifestyle factors can further exacerbate genomic instability and epigenetic drift, thereby promoting carcinogenesis. Dysregulation of transcriptional networks and cell-cycle checkpoints—integrative hubs for oncogenic signalling—remains fundamental to cancer progression (10,11).

MNAT1 and cell cycle

The cell cycle is governed by CDKs, which require activation by the CAK complex. CAK phosphorylates CDKs at key threonine residues (e.g., Thr160/161), thereby enabling phase transitions such as the G1–S and G2–M checkpoints, driving Rb hyperphosphorylation and E2F release (12-14). This activation process is further coordinated by other core regulators, including cdc25 phosphatases that remove inhibitory phosphorylations, and ubiquitin ligases such as Skp1-Cullin-F-box (SCF) and anaphase-promoting complex/cyclosome (APC/C) that control cyclin stability, together ensuring precise CDK activity throughout the cell cycle (15-18). MNAT1 is a structural and regulatory CAK subunit that stabilizes the CDK7-cyclin H interaction and supports CAK assembly and activity. By promoting CAK-mediated CDK activation, MNAT1 contributes to coordinated cell-cycle progression and maintenance of genomic integrity (19,20). Conversely, MNAT1 dysregulation can destabilize CAK, impair CDK activation, and alter checkpoint control, collectively promoting tumour-associated proliferation (Figure 1).

Figure 1 The role of MNAT1 in regulating the cell cycle. This is an original schematic illustration created by the authors. APC/C, anaphase-promoting complex/cyclosome; CAK, CDK-activating kinase; Cdc25A/B, cell division cycle 25A/B; CDK, cyclin-dependent kinase; DP1/2, transcription factor DP1/2; E2F, E2F transcription factor 1; MNAT1, Ménage à trois 1; P, phosphorylation; Rb, retinoblastoma; SCF, Skp1-Cullin-F-box; U, ubiquitination.

In pancreatic cancer models, siRNA-mediated MNAT1 silencing markedly destabilizes the CAK complex, induces G1-phase cell cycle arrest, and effectively suppresses malignant proliferation and tumor growth (21,22). In colorectal cancer, MNAT1 is frequently overexpressed, drives aberrant cell cycle progression, participates in tumor diagnosis, and facilitates malignant proliferation, with high expression indicating unfavorable clinical prognosis (23). Consistently, aberrant MNAT1 dysregulation is closely involved in tumor proliferation, cell cycle disorder and clinical progression of esophageal and upper aerodigestive tract squamous cell carcinoma (24,25), and comparable expression patterns and prognostic relevance are also observed in gastric cancer (26). Similar oncogenic roles of MNAT1 in regulating cell cycle have also been observed in breast cancer, osteosarcoma and leukemia, implying a pan-cancer conserved regulatory mechanism in cell cycle control (3,4,27). Collectively, these findings position MNAT1 as a nexus linking CAK function to oncogenic cell-cycle dysregulation and support MNAT1/CAK as a therapeutic vulnerability in cancers driven by CDK-dependent signaling (28-31).

MNAT1 and transcription

Beyond its role in cell-cycle control, CAK contributes to transcription through phosphorylation of the Pol II CTD, thereby linking proliferation to transcriptional regulation (14). TFIIH is a multisubunit complex essential for Pol II transcription initiation and NER and comprises a core subcomplex plus the CAK module (32,33). Supported by MNAT1, CDK7 phosphorylates Pol II CTD Ser5, which is critical for promoter escape and early elongation (34,35). MNAT1 stabilizes CAK assembly and CDK7 kinase activity by maintaining the CDK7-cyclin H interaction and supporting proper CAK conformation (35-37). Accordingly, MNAT1 depletion compromises CDK7-dependent CTD phosphorylation and can disrupt transcription initiation, mRNA synthesis, and downstream RNA process (35). In addition to CDK7-mediated initiation control, transcription elongation and splicing are further coordinated by related CDKs (Figure 2). CDK9 phosphorylates Pol II CTD to drive elongation, while CDK11 regulates pre-mRNA splicing via SF3B1 phosphorylation (38-40). Notably, CDK8 lacks the conserved T-loop threonine and is not activated by CAK, instead functioning as a mediator-associated kinase to regulate transcription (41).

Figure 2 The role of MNAT1 in regulating the transcription. This is an original schematic illustration created by the authors. CAK, CDK-activating kinase; CDK, cyclin-dependent kinase; DSIF, DRB sensitivity-inducing factor; MNAT1, Ménage à trois 1; NELF, negative elongation factor; P, phosphorylation; Pol II, polymerase II; SF3B1, splicing factor 3b subunit 1; TFIIH, transcription factor II H; XPB, xeroderma pigmentosum group B; XPD, xeroderma pigmentosum group D.

MNAT1/TFIIH dysregulation has been linked to cancer and other pathological states. In digestive cancers, SMYD2-mediated epigenetic upregulation of MNAT1 activates PI3K/AKT cascade and facilitates malignant progression of pancreatic adenocarcinoma (21). Aberrant MNAT1 expression also disturbs oncogenic transcriptional programs and aggravates tumor deterioration in upper digestive tract squamous cell carcinoma (24). Apart from GI tumors, MNAT1 exerts broad transcriptional regulatory effects in other malignancies. It mediates transcription of apoptosis-related genes to reverse chemoresistance in laryngeal squamous cell carcinoma (25). TFIIH-associated MNAT1 expression is closely associated with clinical prognosis of prostate cancer (42). Abnormal MNAT1 transcriptional control interrupts cell differentiation and accelerates proliferation and metastasis of leukemic myeloblasts (27). Collectively, these findings establish MNAT1 as a pivotal transcriptional regulator across diverse cancers, with context-dependent oncogenic roles.

MNAT1 and immune modulation

Growing evidence suggests that MNAT1 may influence anti-tumour immunity by reshaping the tumour immune microenvironment through transcriptional programs and downstream cytokine signaling (Figure 3A). Transcription-associated CDKs are increasingly recognized as key regulators of immune-related gene programs in GI cancers, and targeting this axis represents a promising strategy to reverse immune evasion (43). Mechanistically, CDK7 inhibition downregulates programmed death-ligand 1 (PD-L1) transcription and expression, relieving immune suppression and enhancing anti-programmed death-1 (PD-1) therapy efficacy (44). In gastric cancer, high PD-L1 expression is closely correlated with reduced CD8⁺ T cell infiltration and unfavorable patient outcomes, confirming the link between this transcriptional pathway and impaired anti-tumor immunity (45). Beyond direct regulation of T cell function, MNAT1-related pathways also influence other immune components, such as M2-like tumor-associated macrophages (TAMs), which contribute to immunosuppression and therapy resistance in the tumour microenvironment (TME) (46). Notably, PD-L1 function is further modulated by post-translational modifications, such as deglycosylation, which can alter its localization and downstream DNA repair processes, adding another layer of complexity to MNAT1-mediated immune regulation (47). Collectively, these findings highlight MNAT1 as a central node linking transcriptional control to multiple immunosuppressive mechanisms in the TME, with important implications for immunotherapy in digestive malignancies.

Figure 3 MNAT1-mediated interactive network. (A) MNAT1 promotes tumour immune evasion by enhancing TFIIH/CAK-mediated phosphorylation of Pol II, which upregulates PD-L1 expression and suppresses CD8⁺ T cell infiltration into the TME; (B) MNAT1 supports NER of DNA damage by coordinating repair enzymes (XPB, XPD) and DNA polymerase activity; (C) MNAT1 drives HIF-1α gene transcription, upregulating glycolytic enzymes and PEP production. Increased PEP promotes lactylation of TAMs, leading to their polarization toward the pro-tumorigenic M2 phenotype. This is an original schematic illustration created by the authors. CAK, CDK-activating kinase; CDK, cyclin-dependent kinase; HIF-1α, hypoxia-inducible factor 1-alpha; MNAT1, Ménage à trois 1; NER, nucleotide excision repair; P, phosphorylation; PD-1, programmed death-1; PD-L1, programmed death-ligand 1; PEP, phosphoenolpyruvate; Pol II, polymerase II; TAMs, tumor-associated macrophages; TFIIH, transcription factor II H; TME, tumour microenvironment; XPB, xeroderma pigmentosum group B; XPD, xeroderma pigmentosum group D.

MNAT1 and DNA repair

TFIIH is a core component of the NER pathway, which repairs bulky DNA lesions and maintains genome integrity (48). As an essential structural subunit, MNAT1 stabilizes the TFIIH complex and is therefore poised to influence DNA repair capacity and treatment response (Figure 3B). During NER, TFIIH unwinds damaged DNA and serves as a platform for the assembly of repair enzymes, and the CAK module is anchored to the core TFIIH complex in a helicase-dependent manner—a process disrupted in xeroderma pigmentosum group B (XPB)/CS fibroblasts due to impaired XPB function (36). In GI cancers, functional TFIIH components including ERCC2/xeroderma pigmentosum group D (XPD) are associated with sensitivity to DNA-damaging chemotherapies, highlighting the clinical relevance of this repair pathway (49). By preserving TFIIH integrity, MNAT1 ensures efficient DNA damage recognition and repair, thereby sustaining genomic stability in tumour cells.

Given its role in maintaining TFIIH integrity, MNAT1/CAK disruption may sensitize tumours to DNA-damaging agents by weakening repair programs. Consistent with this rationale, inhibition of CAK-related functions has been proposed to enhance responses to platinum-based therapy and to increase vulnerability to PARP inhibition by impairing repair and replication-stress handling (50,51). Overall, MNAT1’s positioning at the interface of transcription and DNA repair supports its potential relevance to strategies aimed at overcoming therapy resistance (52,53).

MNAT1 and metabolic reprogramming

MNAT1 may contribute to tumour metabolic plasticity through CAK/TFIIH-dependent transcriptional regulation and downstream pathway crosstalk. As a component of the CAK module, MNAT1 can influence transcriptional programs that govern mitochondrial function and energy metabolism (Figure 3C). MNAT1 modulates the transcription of critical metabolic regulators, including HIF-1α and PPARγ coactivator 1 (PGC-1α), thereby influencing both glycolytic and oxidative metabolism programs (42,43). By supporting TFIIH-dependent transcription, MNAT1 promotes the expression of HIF-1α and downstream glycolytic enzymes, enhancing glycolytic flux and increasing the production of phosphoenolpyruvate (PEP). Elevated glycolytic activity and lactate accumulation drive lactylation-mediated signaling in TAMs, promoting their polarization toward an immunosuppressive M2 phenotype (54,55). Notably, MNAT1 also plays a conserved role in suppressing oxidative metabolism by inhibiting PGC-1α function, shifting cellular energy production toward glycolysis—a hallmark of cancer cells (9). This coordinated metabolic rewiring not only sustains tumor cell proliferation but also shapes an immune-suppressive microenvironment, underscoring MNAT1’s central role in linking transcription, metabolism, and immunological adaptations in malignancies (46).

MNAT1 as a therapeutic targeting

As a distinctive non-enzymatic structural subunit of the CAK-TFIIH complex, MNAT1 functions as an active regulator rather than a mere scaffold. It independently preserves complex stability, orchestrates CAK assembly and subcellular localization, and modulates downstream transcriptional and cell-cycle programs in GI cancers. Distinct from the kinase-dependent functions of CDK7, MNAT1 exerts specific biological effects that cannot be fully recapitulated by single CDK7 inhibition (29,52). Given its dysregulated expression and oncogenic role in gastric, colorectal, pancreatic, and oesophageal cancers, MNAT1/CAK axis has emerged as a promising therapeutic vulnerability for GI malignancies. Current therapeutic approaches encompass CDK7-targeted interventions, MNAT1-specific targeting, and rational combination regimens.

Direct targeting strategies

MNAT1 gene silencing

Different from CDK7 inhibitors that act on kinase activity, targeting MNAT1 represents an independent, distinctive therapeutic strategy relying on its non-enzymatic regulatory function. Perturbing MNAT1 expression via RNAi, CRISPR-Cas9 or disrupting the MNAT1-CDK7 interaction has been demonstrated to result in the collapse of CAK complex integrity, the indirect abolition of CDK7 activity and the broad inhibition of downstream oncogenic signalling cascades (Figure 4).

Figure 4 The principle of direct targeting strategies. MNAT1 gene knockdown disrupts complex assembly and stability, while CDK7 inhibitors block the kinase activity of the complex, thereby inhibiting both downstream pathways. This is an original schematic illustration created by the authors. CDK, cyclin-dependent kinase; CTD, C-terminal domain; DP1/2, transcription factor DP1/2; E2F, E2F transcription factor 1; MNAT1, Ménage à trois 1; P, phosphorylation; Pol II, polymerase II; Rb, retinoblastoma.

In GI tumours, MNAT1 silencing yields prominent anti-tumour efficacy. In pancreatic cancer, SMYD2-mediated epigenetic upregulation of MNAT1 activates the PI3K/AKT cascade and drives malignant progression, and MNAT1 depletion destabilizes the CAK complex, induces G1-phase cell cycle arrest, elevates DNA damage markers, and enhances chemosensitivity to DNA-damaging agents (21,56). In colorectal cancer, high MNAT1 expression correlates with aberrant cell-cycle progression, unfavourable prognosis, and resistance to irinotecan, and downregulation of MNAT1 restrains tumour proliferation and reverses chemotherapy resistance (57). For gastric and oesophageal cancers, MNAT1 interference also suppresses tumour proliferation and malignant progression, likely through disrupting TFIIH-dependent transcription and DNA repair (24).

Notably, MNAT1-targeted therapy exhibits unique advantages over single CDK7 inhibition: it comprehensively dismantles TFIIH-related transcription, DNA repair and immune regulatory pathways, and reduces off-target toxicity caused by non-selective CDK7 blockade (35). Nevertheless, translational challenges remain, including delivery efficiency and tumour-specific enrichment. Nanoparticle-based delivery systems provide a feasible solution for MNAT1 siRNA or targeted agents, laying a foundation for subsequent clinical transformation.

CDK7 inhibitors

The majority of contemporary preclinical and pharmacological studies concentrate on CDK7 inhibitors, which primarily suppress the catalytic kinase activity of CAK as opposed to MNAT1-specific functions. By impeding CDK7-mediated RNA Pol II phosphorylation and cell-cycle CDK activation, these agents effectively inhibit oncogenic transcription addiction and cell-cycle progression, consequently inducing growth arrest and apoptosis in transcription-dependent tumour cells (Figure 4) (44,48,58,59). CDK7 also crosstalks with CDK9 and CDK12 to broaden anti-tumour action, emphasizing the importance of defining tumour-specific vulnerabilities (42,60).

In GI cancers, CDK7 inhibition has demonstrated significant preclinical relevance. For instance, the targeting of the CDK7 axis has been demonstrated to reverse irinotecan resistance in colorectal cancer and to suppress malignant progression of pancreatic tumours (57). Beyond GI tumours, relevant studies on CDK7 inhibition has also been conducted in breast and prostate cancers (58,60,61). Collectively, CDK7 inhibitors represent a general CAK-targeted strategy for GI cancers, with ongoing studies investigating the optimisation of drug selectivity, delivery systems, and clinical tolerability, see Table 2.

Combination treatment strategies

Combination therapies are increasingly explored to enhance MNAT1/CAK-targeting efficacy and to overcome resistance mechanisms driven by transcriptional dysregulation (43). Rational regimens combine MNAT1/CAK perturbation with chemotherapy, targeted therapy and immune checkpoint blockade to produce synergistic anti-tumor activity, see Table 3.

In colorectal cancer, MNAT1/CAK axis inhibition sensitizes tumor cells to irinotecan and oxaliplatin, reversing chemoresistance via impaired DNA repair and transcriptional adaptation (6,57). In pancreatic cancer, MNAT1/CDK7 targeting combined with gemcitabine suppresses desmoplastic stroma formation and blocks PI3K/AKT-mediated malignant progression (21,48). In gastric cancer, MNAT1-associated transcriptional networks modulate PD-L1 expression and M2 macrophage polarization; CDK7 inhibition strengthens anti-PD-1 immunotherapy efficacy by remodeling the immunosuppressive microenvironment (44-46). For GI stromal tumors (GISTs), MNAT1/CDK7 targeting inhibits c-KIT transcription, potentiates imatinib efficacy and delays the emergence of drug resistance (62). Collectively, these GI cancer-based evidences indicate that MNAT1/CAK-targeted combination therapy exploits tumor vulnerabilities including defective DNA repair, transcriptional addiction and immune escape. Optimizing biomarker-guided combination schemes will further improve the therapeutic window for GI malignancies.

Translational challenges and emerging research

Although MNAT1/CAK-targeting strategies are supported by growing preclinical evidence, translation to the clinic faces several recurring challenges. First, because CAK/TFIIH components are essential for normal cell proliferation and transcription, systemic inhibition can cause dose-limiting toxicities, particularly in rapidly renewing tissues. This highlights the need for therapeutic windows defined by tumour-selective dependence (e.g., transcriptional addiction, high replication stress, or oncogene-driven vulnerability) and for biomarkers that can stratify patients most likely to benefit it (9,27). Second, resistance is likely to emerge through pathway rewiring, compensatory activation of parallel transcriptional kinases (e.g., CDK9/12/13), altered drug efflux, or adaptation of cell-cycle checkpoints (4,56). Third, tissue penetration and intratumour heterogeneity can reduce effective exposure, especially in GI cancers with complex stromal and immune microenvironments (68). Addressing these issues will require integrated pharmacology, biomarker-guided trial design, and rational combinations that exploit induced vulnerabilities rather than relying on single-agent activity.

Nanoparticles

TME-responsive nanoparticles aim to improve tumour selectivity by exploiting local features such as acidic pH, redox imbalance, hypoxia, or enzyme activity to trigger drug release at the disease site. For MNAT1/CAK targeting, nanoparticle platforms are particularly relevant for delivering siRNA/antisense oligonucleotides against MNAT1, or for enhancing tumour accumulation of small-molecule CDK7 inhibitors while limiting systemic exposure (Figure 5A) (69-72). In GI cancers, where stromal barriers can limit drug penetration, advanced formulations (e.g., charge-reversible carriers, mucosal-penetrating coatings, or ligand-directed systems targeting tumour-associated receptors) may help overcome delivery constraints. Importantly, nanoparticle strategies also offer a framework for co-delivery of combination regimens—such as MNAT1/CAK targeting plus DNA-damage agents or immunomodulators—allowing synchronized pharmacokinetics and potentially improving synergy while reducing off-target toxicity.

Figure 5 Mechanisms of action of three emerging technologies targeting MNAT1. (A) pH-responsive nanoparticles deliver MNAT1 siRNA, which is released in the acidic tumour microenvironment to silence MNAT1 gene expression. (B) PROTACs recruit E3 ubiquitin ligases to induce polyubiquitination and proteasomal degradation of MNAT1. (C) AI-optimized anti-MNAT1 antibodies are designed to disrupt MNAT1 interactions with CDK7 or RNA polymerase II, thereby inhibiting its regulatory functions. This is an original schematic illustration created by the authors. AI, artificial intelligence; CDK, cyclin-dependent kinase; MNAT1, Ménage à trois 1; PROTAC, proteolysis-targeting chimera; siRNA, small interfering RNA.

Bivalent degraders

Bivalent degraders [e.g., proteolysis-targeting chimera (PROTACs) and molecular glues] provide an alternative to catalytic inhibition by inducing selective degradation of target proteins via E3 ligase recruitment. This can be advantageous when kinase inhibition is insufficient due to incomplete pathway suppression or rapid feedback reactivation. Degraders may also overcome resistance driven by mutations affecting inhibitor binding while still permitting ubiquitination and proteasomal clearance (Figure 5B) (73). Within the MNAT1/CAK axis, CDK7-targeting degraders have shown the feasibility of dismantling CAK-related functions and suppressing transcriptional output (63). In principle, degradation-based approaches could be extended to other CAK components, or designed to preferentially destabilize CAK in tumour contexts where MNAT1/CAK is overexpressed or structurally engaged in oncogenic complexes. However, key challenges remain, including oral bioavailability, tissue distribution, and potential on-target toxicity in normal proliferative compartments—again underscoring the importance of biomarker-guided patient selection and tumour-selective delivery.

Artificial intelligence (AI) technology

AI and machine-learning approaches are increasingly applied to map MNAT1-centered interaction networks, prioritize druggable interfaces (including protein-protein interactions), and accelerate structure-based discovery of inhibitors and degraders (74,75). For MNAT1/CAK targeting, AI can support (I) identification of tumour subtypes with MNAT1/CAK dependence using multi-omics signatures, (II) prediction of resistance trajectories and rational combination partners, and (III) optimization of compound properties to improve selectivity and reduce off-target effects (Figure 5C). In parallel, AI-enabled analysis of digital pathology and clinical data may help develop predictive biomarkers for trial enrichment. Together, these tools can shorten the path from mechanistic insight to translational strategy—provided that predictions are validated in relevant GI cancer models and clinically annotated cohorts.

Clinical translation hinge points

The clinical translation of MNAT1/CAK-targeting strategies in GI cancers is contingent upon addressing three pivotal translational barriers. Initially, the development of validated, multi-omics-based predictive biomarkers is paramount to delineate patient cohorts with an authentic oncogenic dependency on the MNAT1/CAK axis, thereby enabling precise stratification and enriching clinical trials with likely responders. Subsequently, the formidable drug delivery barriers inherent to GI tumors—notably their dense desmoplastic stroma and immunosuppressive microenvironment—mandate the innovation of tumor-selective delivery platforms (76). Utilizing advanced formulations such as TME-responsive nanocarriers or receptor-targeted systems is critical to enhance the therapeutic index by ensuring sufficient intratumoral drug exposure while sparing normal proliferating tissues. Finally, a preemptive strategy to circumvent acquired resistance is indispensable. Preclinical evidence underscores MNAT1’s role in fostering chemoresistance via disparate mechanisms, including the potentiation of the PI3K/Akt/mTOR pathway in osteosarcoma and the suppression of the GDF15/AMPK-mediated apoptotic cascade in laryngeal squamous cell carcinoma (3,25). Consequently, the systematic investigation of rational combination regimens, which integrate MNAT1/CAK-directed agents with DNA-damaging chemotherapeutics, complementary signaling inhibitors, or immune-checkpoint modulators, is warranted to exploit induced vulnerabilities and forestall resistance. In summary, the synergistic integration of biomarker-guided patient selection, advanced drug delivery technologies, and mechanism-informed combination therapies represents a critical pathway for translating the preclinical promise of MNAT1 targeting into viable precision therapeutics for GI cancers.

Limitations and outlook

Despite the preclinical promise of targeting the MNAT1/CAK axis, its clinical translation in GI cancers faces formidable hurdles, primarily stemming from two interconnected limitations. First, the field’s reliance on conventional cell line and xenograft models fails to fully capture the intricate heterogeneity and dynamic interactions within the native human GI TME. Key features such as the dense desmoplastic stroma, immunosuppressive landscape, and gut microbiota influence—critical for therapy response—are often poorly represented (68,76). This gap undermines the predictive validity of identified biomarkers and therapeutic vulnerabilities. Second, the non-enzymatic, scaffolding function of MNAT1 poses a direct “undruggability” challenge. Current strategies are therefore indirect, focusing on inhibiting its catalytic partner CDK7 or degrading the entire CAK complex (63,77). However, this approach amplifies the risk of on-target, off-tumor toxicity due to the essential roles of CAK/TFIIH in basal transcription and cell cycle progression in healthy tissues (51,52). Thus, defining a tumor-selective therapeutic window is paramount.

To overcome these barriers and steer MNAT1/CAK targeting towards clinical viability, a multi-pronged, technology-driven strategy is essential. Foremost, advancing preclinical models to patient-derived organoids and immunocompetent genetically engineered mouse models is crucial to faithfully recapitulate the GI TME and identify context-dependent synthetic lethal interactions (68,78). Leveraging spatial multi-omics and single-cell technologies will map MNAT1-associated transcriptional networks with cellular resolution (74,79). Concurrently, AI and machine learning should be harnessed to analyze these complex datasets and guide the rational design of next-generation therapeutics, such as allosteric inhibitors or heterobifunctional degraders with enhanced specificity for oncogenic CAK complexes (75). To achieve a viable therapeutic index, the co-development of advanced drug delivery platforms—such as TME-responsive nanoparticles or tumor-targeted formulations—is necessary to maximize intratumoral exposure while minimizing systemic toxicity (69,70). Ultimately, clinical success will likely hinge on rational combination therapies that exploit MNAT1/CAK inhibition-induced vulnerabilities (e.g., impaired DNA repair, modulated immune microenvironment) with standard-of-care agents, within biomarker-stratified patient cohorts (60,67). Through the synergistic integration of biologically relevant models, cutting-edge technologies, and biomarker-guided trial designs, the challenges of targeting MNAT1 can be systematically addressed, paving the way for its potential as a novel precision therapeutic strategy in GI oncology.

Conclusions

This review summarizes the multifaceted roles of the MNAT1/CAK axis in GI cancers, addressing its structural and non-enzymatic regulatory functions, its involvement in cell-cycle progression, transcription, DNA repair, and immune regulation (Figure 6), as well as current and emerging therapeutic strategies that target this axis. The findings highlight MNAT1 as an active, non-scaffold regulator and a promising therapeutic vulnerability that is distinct from CDK7 alone. Collectively, these insights establish a foundation for future basic and translational research focused on developing MNAT1-targeted precision therapies for GI malignancies.

Figure 6 Overview diagram of the mechanism by which MNAT1 affects tumors. CAK, CDK-activating kinase; CDK, cyclin-dependent kinase; DP1/2, transcription factor DP1/2; DSIF, DRB sensitivity-inducing factor; E2F, E2F transcription factor 1; MNAT1, Ménage à trois 1; NELF, negative elongation factor; P, phosphorylation; Pol II, polymerase II; Rb, retinoblastoma; SF3B1, splicing factor 3b subunit 1; TFIIH, transcription factor II H; XPB, xeroderma pigmentosum group B; XPD, xeroderma pigmentosum group D.

Acknowledgments

The authors thank all the members for their support.

Footnote

Reporting Checklist: The authors have completed theNarrative Review reporting checklist. Available at https://jgo.amegroups.com/article/view/10.21037/jgo-2026-1-0186/rc

Peer Review File: Available at https://jgo.amegroups.com/article/view/10.21037/jgo-2026-1-0186/prf

Funding: This work was supported by the Ganzhou Science and Technology Guidance Program (No. GZ2024ZSF838).

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://jgo.amegroups.com/article/view/10.21037/jgo-2026-1-0186/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

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