The roles of STMN3 in various cancers

Abstract

Stathmin-3 (STMN3) is a member of the microtubule-destabilizing regulatory protein family and functions to promote microtubule depolymerization. It specifically binds to the α/β heterodimers of microtubules, facilitating their depolymerization and inhibiting polymerization, thereby influencing cell morphology and function. Recent studies have indicated that aberrant expression of STMN3 is closely associated with the development of various diseases. In the field of oncology, STMN3 has been found to be dysregulated in multiple cancer types and is strongly linked to tumor initiation, progression, and metastasis. Owing to these characteristics, STMN3 is involved in diverse physiological and pathological processes as well as critical signaling pathways, demonstrating its potential as a multifunctional regulatory molecule. This article reviews and analyzes the roles and mechanisms of STMN3 in tumorigenesis, with the aim of identifying potential therapeutic targets and contributing to the development of precision medicine strategies for cancer treatment. This study is a narrative review on the role of STMN3 in tumors, which is guided by the Scale for the Assessment of narrative review articles (SANRA). Literature retrieval was conducted in public databases such as PubMed and Web of Science using “STMN3″, “SCLIP”, “tumor”, and “cancer” as key words, with no restriction on publication time. Relevant studies were screened based on research content and data integrity, including bioinformatic analyses and in vitro/in vivo experimental studies.

Keywords

STMN3 tumor signaling pathways tumor microenvironment biomarker

Basic introduction to STMN3

Stathmin-3 (STMN3), also referred to as SCLIP, is a member of the stathmin-like protein family (STMNs)—a group of highly conserved phosphoproteins in vertebrates known to play important regulatory roles in organ development and function, particularly within the nervous system. The STMN family comprises four major members: STMN1 (Op18/Pro18), STMN2 (SCG10), STMN3 (SCLIP), and STMN4 (RB3). These proteins share significant structural and functional homology.¹

All STMN proteins contain a stathmin-like domain (SLD), which consists of two key regions:An N-terminal regulatory domain featuring conserved phosphorylation sites that are targeted by kinases within intracellular signaling cascades; A C-terminal interaction domain characterized by an α-helical structure, which mediates binding to various protein partners and influences diverse cellular functions.² In STMN1 and STMN3,the drgree of similarity of the two sub-domains varies aiong the suquence.

STMN1 was the first protein identified in the stathmin family. Comprising 149 amino acids, it is the shortest protein within the family in terms of sequence length and has served as the foundational model for much of the research on STMNs. Four phosphorylation sites have been characterized within its stathmin-like domain (SLD): Ser16, Ser25, Ser38, and Ser63. Among these, Ser16 is phosphorylated by CaMK kinase, Ser25 serves as a substrate for MAPKs, Ser38 is targeted by CDK2, and Ser63 is phosphorylated by PKA. In comparison, STMN3 consists of 180 amino acids and features an additional structural segment at its N-terminus. Within the SLD of STMN3, phosphorylation sites functionally analogous to Ser16, Ser38, and Ser63 have also been identified.³(Figure 1).

Figure 1.

Structure diagram of STMN1 and STMN3 as well as their related signal patterns.

The microtubule-depolymerizing activity of STMNs is primarily mediated through their SLD. Current studies indicate that all STMNs proteins (P) can interact with soluble tubulin heterodimers (T) to form a T₂P complex, which sequesters tubulin and thereby disrupts microtubule assembly and stability. This interaction is modulated by phosphorylation at specific sites within the SLD.

Furthermore, the N-terminal extensions of STMN proteins contain distinct regulatory motifs. For example, palmitoylation of two adjacent cysteine residues in the membrane-targeting domain facilitates anchoring to cellular membranes, influencing the subcellular localization of each STMN member. As a result, different STMNs exhibit varying distributions within the cell. In embryonic cortical neurons, STMN1 is widely distributed throughout the cell body, dendrites, axons, and growth cones. In contrast, other STMN family members such as STMN2, STMN3, and STMN4 are predominantly localized to the Golgi apparatus, though they are also present in dendrites, axons, and growth cones.⁴ Functionally, STMN1 contributes broadly to neuronal formation and maturation; STMN2 is implicated in growth cone expansion and axon elongation.^5,6 while STMN3 plays a specific role in regulating axon branching and dendritic maturation.^7,8

STMN1 exhibits broad expression across human tissues, with particularly high levels observed in the nervous system—including the brain, spinal cord, and cerebellum. It is also strongly expressed in hematopoietic tissues such as the thymus, bone marrow, testis, and fetal liver. Elevated expression is further detected in the colon, ovary, placenta, uterus, and trachea. In other tissues, STMN1 mRNA is present but generally at low levels, with the lowest expression found in the adult liver.

In contrast, the expression of STMN2 and STMN4 demonstrates notable neural specificity. These proteins are only minimally expressed in non-neural tissues, with faint detection reported in the colon, small intestine, adrenal gland, and prostate.

Initially, STMN3 was also believed to be neural-specific; however, subsequent studies have revealed its expression across all major tissues. It is especially abundant in the brain, spinal cord, cerebellum, thymus, and thyroid.⁹ The expression profile of STMN3 closely parallels that of STMN1, suggesting that the two proteins may function synergistically or provide functional redundancy in certain biological contexts.

Research on the correlation between STMN3 and tumors

In recent years, accumulating evidence from numerous studies has demonstrated that STMNs are aberrantly expressed in a wide spectrum of tumors, with their expression levels closely correlated with tumor malignant potential, clinical outcomes, and therapeutic responsiveness. Among all STMN family members, STMN1 has been the most extensively investigated. It is well-documented that STMN1 is significantly overexpressed in various malignant tumors and intimately involved in critical tumor biological processes, including cell proliferation,¹⁰ apoptosis,¹¹ migration,¹² invasion and angiogenesis.¹³ However, recent studies on the correlation between STMN3 and tumors remain relatively limited. Available research can be broadly categorized into two types: bioinformatic analyses that lack validation through in vivo or in vitro experiments (Table 1), and experimental studies that examine STMN3 expression at both cellular and tissue levels (Table 2).

Table 1.

Summary of bioinfomatics analysis studies on STMN3.

Publications	Cancer type	Data source	Techniques	Notes
Shen C¹⁴	bladder cancer	TCGA,	LASSO Cox regression,	STMN3 is highly expressed in bladder cancer and exerts a promotive effect on the initiation and progression of bladder cancer by modulating the tumor microenvironment.
		GEO, IMvigor210, MSigDB,	GSEA,
		TIDE	IPS
Kwak Y¹⁵	MANEC	Seoul National University Bundang Hospital and Seoul National University	GeoMx DSP.	STMN3 protein expression was significantly higher in the NEC component than in the ADC component, driving fibrosis and immunosuppression in the NEC tumor microenvironment.
Kwak Y¹⁵	MANEC	Hospital	Deconvolution analysis
Saunders CN¹⁶	glioma	ENGAGE,	SMR	The STMN3 gene mutation leads to longer leukocyte telomere length and increases the risk of glioma occurrence.
Saunders CN¹⁶	glioma	EPIC-CVD	SMR
Labreche K¹⁷	glioma	TCGA,	SNPTESTv2.5,Cox regression,	Overexpression of STMN3 promotes growth in glioma cells.
		French-GWAS,	Hi-C,
		French sequencing	GSEA
Robinson JW¹⁸	glioma	GTEX,	SMR	STMN3 expression is correlated with glioma initiation, whereas the effects of STMN3 expression in brain and blood tissues on the risk of glioma development are divergent.
		ROSMAP,
		CMC
Wang T¹⁹	NSCLC	TCGA	LASSO Cox regression,	STMN3 can be applied to diagnose the hot and cold tumor subtype to indicate the treatment response of PD-1/PD-L1 inhibitor in NSCLC.
			SVM,
			GMM,
			CIBERSORT,
			ConsensusClusterPlus
Cheng WS²⁰	Prostate cancer	SRA	TopHat,	STMN3 is highly expressed in prostate cancer and can be applied to distinguish between benign and maligant tumors.
Cheng WS²⁰	Prostate cancer	SRA	GSEA
Zheng K²¹	bladder cancer	TCGA,	WGCNA,	Overexpression of STMN3 is associated with the proliferation of cancer-associated fibroblasts and leads to poor prognosis in bladder cancer.
Zheng K²¹	bladder cancer	GEO	LASSO Cox regression,GSEA

ENGAGE: European Network for Genetic and Genomic Epidemiology; EPIC-CVD: European Prospective Investigation into Cancer; SMR: Summary - based Mendelian Randomization; TCGA: The Cancer Genome Atlas; GWAS: Genome - Wide Association Study; Hi-C: High-throughput chromosome conformation capture; GSEA: Gene Set Enrichment Analysis; GTEX: Genotype-Tissue Expression; ROSMAP: Religious Orders Study and Memory and Aging Project; CMC: CommonMind Consortium; GEO: Gene Expression Omnibus; TIDE: Tumor Immune Dysfunction and Exclusion; NSCLC: Non-small cell lung cancer; IPS: Immunophenotype Score; WGCNA: Weighted Gene Co-Expression Network Analysis; SVM: Support Vector Machine; GMM: Gaussian Mixture Model; SRA: Sequence Read Archive; MANEC:mixed adenoneuroendocrine carcinoma; NEC: neuroendocrine carcinoma; ADC: adenocarcinoma.

Table 2.

Summary of experimental studies on STMN3.

Publications	Cancer type	Cell lines	Tissue	Techniques	Notes
Ng DC²²	Breast cancer	Yes	No	WB,qRT-PCR,FCM,IF	STMN3 is a STAT3-interacting protein involved in maintaining epithelial morphology in MCF-7 breast cancer cells.
Zhang Y²³	glioma	Yes	Yes	IHC,WB, qRT-PCRFCM	STMN3 is overexpressed in glioma, and the downregulation of STMN3 expression suppresses the proliferation, migration and invasion of glioma cells in vitro.
Li L²⁴	CML	Yes	No	WB,qRT-PCR,FCM	STMN3 is a direct downstream factor of STAT3, regulates Bcl-2 and cyclin E1 and mediates the viability and apoptosis of CML cells.
Singer S²⁵	NSCLC	Yes	Yes	IHC,WB, qRT-PCR	STMN3 is overexpressed in both adenocarcinoma and squamous cell carcinoma tissues and promotes the proliferation, migration and matrix invasion of tumor cells.
Singer S²⁵	NSCLC	Yes	Yes	FCM,IF
Nair S²⁶	NSCLC	Yes	No	WB,IF qRT-PCR	Nicotine promotes invasion and migration of non-small cell lung carcinoma cells by modulating STMN3 and GSPT1 in an ID1-dependent manner.
Xie X²⁷	ovarian cancer	Yes	No	WB,qRT-PCR,FCM	Bisphosphorylated PEA-15 sensitizes ovarian cancer cells to paclitaxel by attenuating the microtubule-destabilizing activity of STMN3.
Fang F²⁸	Breast cancer	Yes	Yes	IHC,WB, qRT-PCR	Knockdown of CypB in breast cancer decreases STMN3 expression and leads to reduced cell motility.
Fang F²⁸	Breast cancer	Yes	Yes	FCM,IF
Zou C²⁹	Cervical cancer	No	Yes	TCT test,	The expression level of STMN3 in peripheral blood can be used to distinguish cervical HSIL from LSIL.
Zou C²⁹	Cervical cancer	No	Yes	Microarray hybridization, AdaBoost
Lips EH³⁰	Rectal cancer	No	Yes	qRT-PCR	STMN3 is highly expressed in rectal cancer and may be associated with tumor progression and poor prognosis.
Lips EH³⁰	Rectal cancer	No	Yes	ICH, Microarray hybridization

IHC: immunohistochemistry; WB: western-blot; qRT-PCR: quantitative Real-Time Polymerase Chain Reaction; FCM: flow cytometry; IF:immunofluorescence; TCT test: thinprep cytological test; CML: Chronic myeloid leukemia.

Current findings indicate that STMN3 is highly expressed in multiple human malignancies, including glioma, bladder cancer, non-small cell lung cancer, prostate cancer, chronic myeloid leukemia, breast cancer, ovarian cancer, cervical cancer, and colorectal cancer. Moreover, elevated STMN3 expression is closely associated with malignant biological behaviors—such as proliferation, invasion, and metastasis—as well as adverse clinical characteristics in these cancers.

Mechanisms by which STMN3 affects tumorigenesis and development

The STAT3/STMN3 signaling pathway

Signal transducer and activator of transcription 3 (STAT3) is a member of the STAT family of cytoplasmic transcription factors. It is well established that STAT3 mediates multiple intracellular signaling pathways³¹ and participates in numerous biological processes such as cell proliferation, migration, and angiogenesis.³²

In a study on STAT3, the C-terminal region of Stat3 (AAs 395–770) was used as a bait. Through a yeast two-hybrid screen of a mouse brain library, STMN3 was identified as an interacting protein of Stat3. Subsequently, the interaction between the exogenously expressed proteins was confirmed in mammalian COS-1 cells.³³ STAT3 interacts with the C-terminal domain of STMN3, and both proteins colocalize in the Golgi apparatus, forming a stable protein complex under physiological conditions. STAT3 regulates STMN3 not through transcriptional control but primarily by maintaining its protein stability, and this regulatory effect is modulated by the activation state of STAT3.²² Unphosphorylated STAT3 stably binds to STMN3. Following STAT3 phosphorylation induced by the STAT3 inhibitor JSI-124, the stability of the STAT3-STMN3 interaction significantly decreased, while STMN3 protein degradation markedly increased. STAT3 knockdown experiments revealed that its downregulation did not affect STMN3 mRNA expression levels, further confirming that STAT3 regulation of STMN3 does not involve transcriptional control.²³ After forming a stable complex with STAT3, STMN3 mediates multiple biological functions, and the regulatory role of this complex exhibits specificity across different tumor cell types. In breast cancer cells, the STAT3-STMN3 complex stabilizes intercellular adhesion junctions by maintaining E-cadherin expression levels. When STAT3 is activated or STMN3 is knocked down, breast cancer cells lose epithelial morphology and undergo accelerated mesenchymal transition. In glioblastoma cells, the STAT3-STMN3 complex significantly enhances cell migration and invasion capabilities. Knocking down STMN3 reduces glioblastoma cell migration by 30–50% and invasion by 40–60%. In chronic myeloid leukemia, the STAT3-STMN3 complex further regulates the expression of Bcl-2 and cyclin E1, forming a STAT3→STMN3→Bcl-2/cyclin E1 signaling regulatory axis that promotes tumor cell proliferation, migration, and anti-apoptotic capacity.²⁴

The nicotine/ID1/STMN3 pathway

Inhibitor of DNA binding/differentiation 1 (ID1) belongs to the helix-loop-helix family of transcription factors. The ID1 gene does not fully meet the classic definition of an oncogene. With the exception of some cases of Burkitt lymphoma, current research has not identified any tumor-associated mutations in this gene.³⁴ However, the ID1 protein is abnormally overexpressed in more than 20 types of malignant tumors, including breast, prostate, pancreatic, and lung cancers, and is regarded as a tumor initiator.²⁵ Numerous studies have demonstrated that ID1 promotes tumor proliferation and metastasis, potently induces angiogenesis and epithelial-mesenchymal transition, and participates in regulating tumor resistance to chemotherapy and tolerance to radiotherapy,³⁵ making it a highly promising anti-tumor therapeutic target.

A study on non-small cell lung cancer (NSCLC) revealed that nicotine activates nicotinic acetylcholine receptors (nAChR) on the surface of NSCLC cells, while epidermal growth factor (EGF) activates its receptor, the epidermal growth factor receptor (EGFR). Both activate distinct downstream signaling pathways. Both signaling pathways induce the upregulation of inhibitor of differentiation 1 (ID1) through Src kinase-dependent regulation. As a key regulatory molecule, ID1 suppresses the functions of neuron-restrictive silencer factor (NRSF) and zinc-binding protein 89 (ZBP89), thereby releasing the transcriptional repression of STMN3 and GSPT1 genes by these two co-inhibitors and promoting their expression. High STMN3 expression enhances NSCLC cell proliferation, invasion, and migration capabilities, driving malignant tumor progression. Beyond its classical role in protein translation termination, GSPT1 modulates cell cycle processes and apoptosis signaling pathways. It synergistically interacts with STMN3 to further amplify the malignant phenotype of NSCLC cells, accelerating tumorigenesis and progression.²⁶

This study investigates how nicotine and EGF induce ID1 expression through a Src kinase-dependent pathway. ID1 then relieves transcriptional repression on STMN3 and GSPT1 by inhibiting NRSF/ZBP89, with both genes synergistically enhancing the malignant phenotype of NSCLC. This provides new targets and theoretical basis for NSCLC pathogenesis research and targeted therapy. However, this study did not utilize animal experiments, did not assess STMN3 expression levels in clinical NSCLC samples, nor did it analyze its correlation with patient clinical-pathological characteristics and prognosis. Analysis based solely on cell lines regarding STMN3’s role in NSCLC development remains somewhat limited.

Role of STMN3 in paclitaxel chemosensitivity

Paclitaxel is a widely used chemotherapeutic agent that binds to the β-subunit of tubulin, promoting microtubule polymerization and stabilizing the microtubule network. By disrupting normal microtubule dynamics and impairing mitotic spindle formation, paclitaxel induces cell cycle arrest at the G2/M phase and triggers programmed cell death.³⁶ Current research indicates that high STMN1 expression is closely associated with paclitaxel resistance, and inhibiting its expression can significantly enhance the sensitivity of tumor cells to paclitaxel chemotherapy. This phenomenon has been confirmed in various types of cancer, including NSCLC,³⁷ breast cancer,³⁸ and esophageal cancer.³⁹ However, there has been limited research to date on the association between paclitaxel resistance and STMN3.

Phosphoprotein enriched in astrocytes 15 (PEA-15) is a multifunctional protein involved in the regulation of cell proliferation, autophagy, and glucose metabolism. Its biological activity is highly dependent on its phosphorylation status.⁴⁰ Studies in ovarian cancer cells have shown that overexpression of phosphorylated PEA-15 (pPEA-15) enhances paclitaxel-induced microtubule polymerization and stabilization.

Notably, ovarian cancer cells with high pPEA-15 expression exhibit elevated basal levels of STMN3. However, following paclitaxel treatment, these cells show a more pronounced reduction in STMN3 protein levels. This downregulation correlates with enhanced paclitaxel efficacy, including increased mitotic arrest and apoptosis.²⁷ These results suggest that pPEA-15 may antagonize the microtubule-destabilizing function of STMN3, thereby amplifying paclitaxel’s effects on microtubule stabilization and ultimately strengthening its anti-tumor activity in ovarian cancer.

The relationship between STMN3 and the tumor microenvironment

The tumor microenvironment (TME) refers to the internal milieu in which tumor cells originate and thrive. It encompasses not only the tumor cells themselves but also a complex ecosystem consisting of diverse cellular and non-cellular components. The TME is highly dynamic, characterized by continuous and bidirectional interactions between tumor cells and their surroundings, collectively influencing tumor initiation, progression, immune evasion, metastasis, and response to therapy.

The expression level of STMN3 shows significant correlations with tumor microenvironment cold/hot profiling, immune cell infiltration characteristics, and patient prognosis, demonstrating a consistent pro-tumorigenic trend across multiple cancer types. In bladder cancer studies, patients with high STMN3 expression were classified as high-risk individuals. These patients exhibited significantly increased infiltration of immunosuppressive cells—including myeloid-derived suppressor cells, mast cells, and regulatory T cells—within their tumor microenvironments, while infiltration of cytotoxic CD8+ T cells was markedly reduced. This ultimately resulted in lower response rates to immune checkpoint inhibitors and significantly shorter overall survival.¹⁴ In non-small cell lung cancer (NSCLC), patients with high STMN3 expression exhibit tumors more likely classified as “cold” tumor phenotypes. These tumor microenvironments feature sparse CD8+ T cell infiltration, downregulated PD-1/PD-L1 expression, and markedly elevated COX-2 expression. COX-2 promotes PGE2 synthesis, thereby inhibiting dendritic cell maturation, reducing CD8+ T cell recruitment to the tumor microenvironment, and inducing macrophage M2 polarization. This collectively establishes a classic immunosuppressive tumor microenvironment.¹⁹ In studies of gastric mixed adenoneuroendocrine carcinoma (MANEC), STMN3 exhibits significantly elevated expression in neuroendocrine carcinoma (NEC) components, with its expression levels closely correlated with tumor microenvironment fibrosis and immune desert phenotypes. In STMN3-overexpressing NEC tissues, fibrosis-related genes such as fibronectin 1 (FN1) and collagen type I alpha 1 chain (COL1A1) show significant enrichment, accompanied by a marked increase in cancer-associated fibroblasts (CAFs). The extracellular matrix (ECM) secreted by CAFs not only physically isolates immune cells from tumor cells but also suppresses the antitumor activity of CD8+ T cells by secreting cytokines like interleukin 6 (IL-6) and transforming growth factor β (TGF-β), ultimately promoting the tumor microenvironment’s progression toward an immune desert phenotype. Compared to the adenocarcinoma (ADC) component in gastric neuroendocrine tumors, the NEC component with high STMN3 expression showed significantly reduced infiltration of effector immune cells, including CD4+ T cells, CD8+ T cells, and B cells, within the epithelium.¹⁵ This finding further validates the close association between high STMN3 expression and the formation of an immunosuppressive tumor microenvironment.

Based on the biological functions of STMN3 and existing research findings, it can be concluded that high STMN3 expression is closely associated with tumor invasive phenotypes and, to a certain extent, positively regulates the formation of an inhibitory tumor microenvironment. However, current studies still face several limitations: First, functional validation experiments following STMN3 knockout or overexpression have not been conducted, resulting in a lack of direct functional evidence; Second, most studies focus on correlation analysis, with insufficient exploration of the molecular mechanisms by which STMN3 regulates tumor invasion and the tumor microenvironment. Third, the diagnostic or prognostic prediction models constructed in these studies have not been independently validated through prospective cohort studies, and their clinical utility requires further confirmation.

Discussion

With the rapid advancement of precision therapy research for malignant tumors, the identification of key molecular targets with regulatory functions has emerged as a central focus in this field. As a crucial member of the microtubule-destabilizing protein family, STMN3 primarily modulates the balance between microtubule polymerization and depolymerization. This dynamic equilibrium of microtubules serves as the cornerstone for essential physiological processes, including cell division, migration, and morphological maintenance, and is closely implicated in tumorigenesis, proliferation, invasion, and metastasis.

In the broader field of cancer research, numerous classic oncogenic drivers and signaling pathways have been thoroughly elucidated. At the same time, the microtubule-disassembling protein family (particularly STMN1) has been widely established as a potent tumor driver and prognostic biomarker in various cancers,⁴¹ including lung, breast, gastric, and liver cancers. However, unlike STMN1, research on STMN3 has long been confined to the field of neurobiology, and its role in tumorigenesis has only gradually been revealed in recent years.

Early studies first identified STMN3 as a member of the microtubule-disassembling protein family enriched in the nervous system, involved in axon branching and dendritic maturation. In several tumor-related studies, bioinformatics screening suggested a potential association with tumorigenesis and progression, and subsequent studies provided experimental validation in glioma, breast cancer, and lung cancer models. These studies established the association between STMN3 and tumors; however, the relevant research remains scattered and tumor-specific.

This article provides a systematic review of the expression levels, regulatory mechanisms, and clinical significance of STMN3 in various malignant tumors, including glioma, bladder cancer, non-small cell lung cancer, breast cancer, and ovarian cancer. Integrated research evidence indicates that STMN3 is abnormally overexpressed in these tumors and can promote tumor proliferation, invasion, metastasis, and immunosuppression. Notably, STMN3 exerts its effects through multiple well-defined pathways: the STAT3/STMN3 pathway stabilizes STMN3 and regulates cell morphology and motility^22–24,34; the nicotinic acetylcholine receptor/ID1/STMN3 pathway drives the progression of non-small cell lung cancer²⁶; and it can modulate tumor sensitivity to paclitaxel by interfering with microtubule stability.²⁷ Furthermore, STMN3 can shape an immunosuppressive tumor microenvironment by reducing CD8+ T-cell infiltration and increasing the number of myeloid suppressor cells and regulatory T cells, thereby mediating resistance to tumor immunotherapy.^15,19,41

This review also has certain limitations, mainly as follows.

(1) Imbalance in research evidence

There are significant discrepancies in the quantity and depth of existing studies on STMN3: research on certain tumors (e.g., NSCLC, glioma) is relatively sufficient, while studies on others (e.g., colorectal cancer, chronic myeloid leukemia) are scarce and lack in-depth mechanistic validation. Furthermore, bioinformatics analysis results account for a relatively high proportion, with some conclusions not validated by in vitro and in vivo experiments.

(2) Insufficient depth of mechanistic research

The mechanistic studies integrated in this review mainly focus on the upstream and downstream interactions of signaling pathways, with inadequate elaboration on the detailed molecular regulatory mechanisms of STMN3 itself. Meanwhile, the specificity and commonality of STMN3’s mechanisms of action across different tumors have not been fully elucidated, and comparative cross-tumor mechanistic analyses are lacking, which hinders an in-depth understanding of its core regulatory functions.

(3) Limitations of clinical sample validation

Most validations based on clinical samples in existing studies are small-sample, single-center investigations, lacking support from large-sample, multi-center clinical cohort data. The diagnostic threshold, prognostic value, and predictive efficacy for chemosensitivity of STMN3 as a biomarker have not been verified in large-scale clinical trials. This not only complicates the accurate assessment of its clinical application potential but also restricts the clinical translational value of the conclusions presented in this review.

(4) Gaps in intervention strategy research

To date, there have been no reports on specific inhibitors or targeted intervention strategies for STMN3. Although this review proposes STMN3 as a potential therapeutic target, the absence of feasible intervention strategies renders the clinical translation pathway unclear.

This article situates STMN3 within the research framework of known tumor drivers and the microtubule-disassembling protein family, highlighting its unique value as a novel complementary biomarker and therapeutic target. Compared to classical oncogenes and STMN1, STMN3 has been found to play a role in multiple aspects, including microtubule dynamics, signal transduction, and tumor immunity, thereby offering a new perspective for research into tumorigenesis and tumor progression.

Conclusion

This study is a narrative review on the role of STMN3 in tumors, which is guided by the Scale for the Assessment of narrative review articles (SANRA).⁴² STMN3 is a key member of the STMN family, primarily functioning to regulate microtubule dynamic equilibrium. STMN3 has been demonstrated to be highly expressed in multiple tumor types, closely associated with tumor cell proliferation, invasion, metastasis, and poor prognosis. It extensively participates in tumorigenesis and progression through signaling pathways such as STAT3/STMN3 and Nicotinic/ID1/STMN3, exerting multifaceted regulatory effects by reshaping the tumor microenvironment and influencing paclitaxel chemotherapy sensitivity. STMN3 holds potential value as both a biomarker and therapeutic target. However, current research faces limitations including limited total volume, incomplete mechanistic understanding, insufficient clinical sample validation, and lack of specific intervention methods. Future efforts should focus on strengthening multicenter clinical validation and targeted drug development to advance its clinical translation and application.

Footnotes

Acknowledgments

We extend our gratitude to all authors of the studies included in this review for providing the foundational data. This manuscript has not been optimized using AI tools for language expression.

ORCID iDs

Jing-jing Yang

Li-zhou Shi

Jie Cheng

Wei-jie Lu

Qing-hua Wang

Wei Han

Author contributions

JY and JC designed the review structure; conducted literature search, selection and synthesis; LS drafted the manuscript. QW and WL Supervised the study.WH critically revised the manuscript for important intellectual content. WH and LS confirm the authenticity of all the raw data. All authors read and approved the final manuscript.approved the final version.

Funding

The authors disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: Young Scientists Fund Project (Category C) of National Natural Science Fundation of China (No. 82503541); Kunshan Major Project of Social Research and Development (No. KS2309; No. KS2308; No. KS2516; No. X25-190-101537; No. KETDCX202405); Suzhou Municipal Bureau on Science and Technology (No. SYW2025030; No. SYW2025169; No. KJXW2023074; No. SKY2023029; No. QNXM2025081); and Jiangsu Provincial Maternal and Child Health Care Association (No. FYX202436; No. FYX202530); Jiangsu University Medical Education Collaborative Innovation Fund (No. JLY2021127; JDYY2023053).

Declaration of conflicting interests

The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Data Availability Statement

This study is a narrative review that did not generate new datasets. All analyzed data were sourced from publicly available literature resources, with relevant references cited according to standard practices in the bibliography.

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