KRT17: A Key Driver of Cancer Therapy Resistance and Emerging Therapeutic Target

Abstract

Keratin 17 (KRT17), a type I intermediate filament protein normally restricted to basal epithelia and hair follicles, is aberrantly overexpressed across diverse aggressive malignancies where it correlates strongly with poor prognosis. Beyond driving core oncogenic processes like cell proliferation, migration, apoptosis evasion, and metabolic reprogramming, KRT17 is increasingly recognized as a pivotal regulator of cancer therapy resistance. Mechanistically, KRT17 induces chemoresistance in multiple cancers through distinct pathways: activating AKT/ERK signaling and epithelial-mesenchymal transition (EMT) in bladder cancer; modulating Wnt/β-catenin in triple-negative breast cancer; influencing the EMT/Snail2/E-cadherin axis in cervical cancer; and engaging FAK/SRC/ERK/CXCL8 immunosuppression in pancreatic cancer. It also contributes to resistance in gastric, thyroid, and skin cancers via EMT, AKT/mTOR, and immune evasion. While KRT17 predominantly drives therapy resistance and immunosuppression across various malignancies, it exhibits a contrasting, context-dependent role in colorectal cancer, where its expression is associated with enhanced T-cell infiltration and improved response to immunotherapy. Given its cancer-specific overexpression, multifaceted role in malignancy (including resistance), and promising preclinical evidence that targeting KRT17 can reverse resistance, KRT17 emerges as a significant diagnostic/prognostic biomarker and a compelling therapeutic target. This review critically synthesizes evidence for KRT17’s role in drug resistance and evaluates its potential for overcoming this major barrier to successful cancer treatment.

Introduction

Cancer remains a leading cause of death worldwide, and the development of drug resistance poses a significant challenge to successful treatment, contributing substantially to cancer-related mortality. Therapy Resistance refers to the ability of cancer cells to become insensitive to anticancer agents, including chemotherapy, targeted therapy, or immunotherapy. It can be categorized as either intrinsic (preexisting) or acquired (developing after initial response). Its mechanisms are complex, encompassing factors such as drug efflux, enhanced DNA damage repair, evasion of apoptosis, and adaptation to the tumor microenvironment. Therefore, unraveling the molecular mechanisms underlying resistance to conventional chemotherapeutics and targeted agents is critical for developing more effective therapeutic strategies.^1,2

Keratin 17 (KRT17), a type I intermediate filament protein primarily expressed in basal epithelial cells and hair follicles, is a tripartite protein comprising 432 amino acids, with a non-helical N-terminal head domain (residues 1–83), a central α-helical domain (residues 84–392), and a non-helical C-terminal tail domain (residues 393–432) (Figure 1). It has emerged as a significant player not only in epithelial structure and function but also in cancer pathogenesis. Aberrant overexpression of KRT17 is a hallmark of aggressive behavior across a remarkably wide range of human malignancies, including lung cancer, cervical cancer, oral squamous cell carcinoma, gastric carcinoma, breast cancer, and sarcoma.^1,3,4 This dysregulated expression is not merely correlative; KRT17 actively contributes to multiple facets of the malignant phenotype. Functional studies reveal its involvement in critical oncogenic processes such as enhanced cell proliferation, growth, migration, evasion of apoptosis, response to mechanical stress, and metabolic reprogramming.^1,2,5 Consequently, high KRT17 expression is frequently associated with advanced tumor stages and poor patient prognosis.^3,4

Figure 1.

KRT17 protein structure. KRT17 is a tripartite protein composed of 432 amino acids, featuring a non-helical N-terminal head domain (residues 1–83), a central α-helical domain (residues 84–392), and a non-helical C-terminal tail domain (residues 393–432).

Importantly, beyond its roles in tumor initiation and progression, compelling evidence positions KRT17 as a key determinant of cancer drug resistance. KRT17 expression has been specifically demonstrated to predict resistance to certain chemotherapeutic agents.² Its contribution to resisting apoptosis and potentially facilitating immune evasion^4,5 provides mechanistic links to therapeutic failure. Given that intermediate filaments are crucial for cellular integrity and response to stress, KRT17 likely contributes to the resilience of cancer cells against cytotoxic insults.

These multifaceted oncogenic roles, particularly its direct implication in treatment resistance, underscore the potential of KRT17 as a valuable therapeutic target. Its consistent overexpression across diverse aggressive cancers, its functional involvement in core hallmarks of cancer (including resistance to cell death), and the presence of targetable domains within the KRT17 protein structure all converge to highlight its promise.^1,2 Targeting KRT17 could potentially reverse drug resistance, enhance the efficacy of existing therapies, or provide a novel standalone treatment avenue.

This review synthesizes current evidence from the scientific literature to critically examine the specific role of KRT17 in driving cancer drug resistance and to evaluate its burgeoning potential as a therapeutic target. We will explore the molecular mechanisms by which KRT17 promotes resistance, analyze its association with specific chemotherapeutic agents, and discuss the challenges and opportunities in developing strategies to therapeutically exploit this critical molecule.

Data Acquisition

We searched PubMed (https://pubmed.ncbi.nlm.nih.gov/) for studies that met the criteria from January 2000 to December 2025. The search terms were set to “(“KRT17” OR “Keratin 17”) AND (“cancer” OR “carcinoma” OR “tumor”)”. The study we included must focus on the role of KRT17 in various cancers, encompassing both its involvement in cancer development and its contribution to cancer resistance. The selection process is shown in a flow diagram (Figure 2).

Figure 2.

Flow diagram of the literature search.

Functional Roles of KRT17 in Various Cancers

Bladder Cancer

KRT17 has been identified as a critical oncoprotein in bladder cancer pathogenesis and therapy resistance. Its overexpression is consistently observed in bladder cancer tissues and cell lines, where it drives malignant progression through multiple mechanistic pathways. Studies demonstrate that KRT17 activates the AKT signaling pathway by promoting phosphorylation at Ser473, which subsequently induces epithelial-mesenchymal transition (EMT) through upregulation of vimentin, N-cadherin, and transcription factors Slug and Twist, while downregulating E-cadherin expression.⁶ This EMT activation enhances tumor cell proliferation, migration, and invasion capabilities, contributing to aggressive disease progression.

The role of KRT17 in chemotherapy resistance is particularly significant. Research shows that KRT17 knockdown markedly reduces phosphorylation of both AKT and ERK pathways, suppressing malignant phenotypes and significantly sensitizing bladder cancer cells to cisplatin treatment.⁷ This sensitization effect is mediated through disruption of key survival pathways and restoration of drug sensitivity mechanisms, providing a strong rationale for targeting KRT17 to overcome chemoresistance in bladder cancer.

Clinically, KRT17 expression shows important prognostic implications. Low KRT17 expression independently correlates with poor prognosis in bladder cancer patients, as indicated by an increased hazard ratio for disease progression.⁸ Its expression levels are strongly associated with advanced tumor grade, T-stage, lymph node metastasis, and overall survival outcomes, making it a valuable prognostic biomarker for risk stratification.

From a diagnostic perspective, KRT17 has demonstrated remarkable utility as a non-invasive biomarker. When combined with MDK, it shows high diagnostic accuracy for non-muscle-invasive bladder cancer (NMIBC) with an AUC of 0.92, sensitivity of 74%, and specificity of 94% in urine-based testing.⁹ This impressive performance highlights its potential for clinical implementation in early detection and monitoring of bladder cancer.

The therapeutic relevance of KRT17 is further underscored by its functional involvement in multiple aspects of bladder cancer biology. Beyond its role in EMT and chemoresistance, KRT17 expression affects cell cycle progression by modulating cyclin E1 and cyclin D expression, potentially influencing tumor proliferation rates.⁸ Additionally, its interaction with various signaling networks suggests that KRT17 occupies a central position in the bladder cancer signaling landscape.

Collectively, these findings position KRT17 as a promising therapeutic target where its inhibition could simultaneously address multiple aspects of bladder cancer malignancy - from overcoming chemoresistance by blocking AKT/ERK activation and reversing EMT, to improving diagnostic precision and prognostic assessment. The multifaceted nature of KRT17’s involvement in bladder cancer pathogenesis underscores its biological significance and highlights its potential as a target for innovative treatment strategies aimed at improving outcomes in this challenging malignancy.

Breast Cancer

KRT17 demonstrates subtype-specific functional roles in breast cancer pathogenesis and therapy resistance,^10–13 with particularly significant implications in triple-negative breast cancer (TNBC). In TNBC, KRT17 is markedly overexpressed and contributes substantially to chemoresistance mechanisms. Research demonstrates that KRT17 expression is significantly elevated in doxorubicin-resistant TNBC cell lines (MDA-MB-468 and MDA-MB-231), where it promotes resistance through regulation of the Wnt/β-catenin signaling pathway.¹⁰ Knockdown of KRT17 expression effectively reverses doxorubicin resistance, reducing half-maximal inhibitory concentration (IC50) values and suppressing cancer cell proliferation, migration, and invasion capabilities. The mechanistic link between KRT17 and Wnt signaling was further established through rescue experiments showing that activation of the Wnt pathway could counteract the inhibitory effects of KRT17 knockdown, confirming this pathway as a primary mechanism through which KRT17 mediates chemoresistance in TNBC.¹⁰

Beyond its role in drug resistance, KRT17 exhibits complex prognostic implications across breast cancer subtypes. While high KRT17 expression correlates with aggressive behavior in TNBC, reduced KRT17 expression predicts poor prognosis specifically in HER2-high breast cancer patients.¹¹ This subtype-dependent duality underscores the context-specific nature of KRT17’s functions in breast cancer pathogenesis. The prognostic value of KRT17 is further supported by its identification as a component of a cuproptosis-related prognostic gene signature in breast cancer, where it contributes to predictive models for patient outcomes.¹³

The tumor microenvironment represents another critical aspect of KRT17’s functionality in breast cancer. Single-cell RNA sequencing analyses have identified KRT17 as one of the genes significantly upregulated in myoepithelial cells (MECs) within TNBC tumors compared to normal breast tissue.¹² This MEC-specific overexpression suggests KRT17 may contribute to tumor progression through modulation of the local microenvironment, potentially influencing stromal-epithelial interactions and immune cell recruitment patterns that support tumor growth and dissemination.

KRT17’s involvement in immune regulation adds another layer to its functional significance. Bioinformatics analyses indicate that KRT17 expression is associated with specific immune cell infiltration patterns, particularly involving natural killer (NK) cells and CD4+ T cells, and is implicated in the regulation of immune-related pathways including the IL-17 signaling pathway.¹¹ These findings suggest that KRT17 may influence the immunologic landscape of breast tumors, potentially affecting response to immunotherapy approaches.

The collective evidence positions KRT17 as a multifunctional regulator in breast cancer biology, influencing drug resistance through Wnt/β-catenin signaling, modulating the tumor microenvironment through myoepithelial cell expression, and contributing to immune response regulation. Its subtype-specific prognostic significance further highlights the complexity of its roles across different breast cancer contexts. These diverse functions make KRT17 a promising therapeutic target, particularly for addressing the challenging problem of chemoresistance in TNBC, while also offering potential as a biomarker for prognosis and treatment response prediction across breast cancer subtypes. Future research directions should focus on developing subtype-specific targeting strategies that account for the dual nature of KRT17’s functions in different breast cancer contexts.

Cervical Cancer

KRT17 plays a critical role in cervical cancer drug resistance and tumor progression, highlighting its potential as a therapeutic target. Research demonstrates that HPV16 infection correlates with elevated KRT17 expression in cervical cancer cells.¹⁴ KRT17 promotes paclitaxel resistance by enhancing cell survival and migration, with knockdown experiments showing sensitization to the cytotoxic effects of paclitaxel and colchicine.¹⁴ Mechanistically, KRT17 drives epithelial-mesenchymal transition (EMT), evidenced by its regulation of Snail2 and E-cadherin.¹⁴ Furthermore, long non-coding RNA MIR205HG modulates KRT17 expression by interacting with splicing factor SRSF1, forming an oncogenic axis that promotes cervical cancer cell proliferation and migration while inhibiting apoptosis.¹⁵ Targeting KRT17 shows therapeutic promise; the natural compound berberine significantly inhibits cervical cancer cell viability, migration, invasion, and EMT progression by downregulating KRT17 expression, concurrently promoting apoptosis through Bax and cleaved caspase-3 activation.¹⁶ Clinically, KRT17 demonstrates diagnostic value as a specific biomarker, being absent in normal cervical tissues yet significantly overexpressed in cervical cancer lesions.¹⁷ Therefore, KRT17’s pivotal role in chemoresistance (particularly to paclitaxel) and metastasis through EMT regulation, combined with its cancer-specific expression profile and vulnerability to pharmacological inhibition (eg, by berberine), highlights its significant potential as a therapeutic target in cervical cancer treatment strategies.

Colorectal Cancer

KRT17 exhibits a complex, context-dependent role in colorectal cancer (CRC) pathogenesis and therapy response, with particularly important implications for immunotherapy resistance and immune microenvironment modulation.¹⁸ Emerging evidence reveals that KRT17 expression significantly influences the tumor immune landscape through regulation of the YTHDF2-CXCL10 axis.¹⁹ Mechanistically, KRT17 promotes the degradation of YTHDF2, an N6-methyladenosine (m6A) “reader” protein, through the ubiquitin-proteasome system. This degradation enhances the stability and expression of CXCL10, a key chemokine that recruits CD8+ T lymphocytes to the tumor microenvironment. This mechanism creates a more favorable immunogenic environment characterized by enhanced T-cell infiltration and activation.¹⁹

The immunomodulatory function of KRT17 has direct therapeutic implications for overcoming immunotherapy resistance. Preclinical studies demonstrate that KRT17 overexpression synergizes with anti-PD-1 therapy, resulting in significantly improved tumor control in immunotherapy-resistant murine CRC models.¹⁹ This synergistic effect is T-cell dependent, as demonstrated by the abrogation of therapeutic benefit upon T-cell depletion. Clinically, patients with high KRT17 expression within their tumors show significantly better responses to pembrolizumab treatment, suggesting that KRT17 expression may serve as a predictive biomarker for immune checkpoint inhibitor response in CRC.¹⁹

A particularly intriguing aspect of KRT17’s function in CRC involves its role in tumor budding (TB), a known histopathological marker of aggressiveness. Contrary to conventional understanding, high KRT17 expression in TB areas is associated with immunologically “hot” tumor buds characterized by abundant CD3+ and CD8+ T-cell infiltration at the invasive margin.²⁰ This specific pattern of KRT17 expression correlates with early tumor stage, absence of lymph node metastasis, and absence of tumor deposits. Most significantly, patients with high KRT17 expression in TB areas demonstrate substantially improved overall survival and disease-free survival compared to those with low KRT17 expression.²⁰

The prognostic significance of KRT17 in CRC exhibits stage-specific characteristics. In stage II CRC, high KRT17 expression (both at mRNA and protein levels) serves as an independent prognostic factor associated with increased risk of postoperative recurrence.²¹ This prognostic value persists even after adjustment for conventional high-risk clinicopathological features, suggesting that KRT17 provides additional risk stratification beyond currently available parameters. The combination of KRT17 with other biomarkers, particularly p27, further enhances prognostic accuracy, with the K17^high/p27^low expression pattern identifying patients with the worst overall survival outcomes.²²

The dual nature of KRT17’s functions in CRC—acting as both a promoter of aggressive features in early-stage disease and a facilitator of antitumor immunity in advanced stages—highlights the complexity of its biological roles. This apparent paradox may be explained by the specific cellular context, tumor microenvironment composition, and molecular interactions that determine KRT17’s net effect on tumor behavior.

From a therapeutic perspective, KRT17 represents a promising target for combination immunotherapy strategies in CRC. Its ability to enhance T-cell infiltration and overcome resistance to immune checkpoint inhibitors suggests that pharmacological modulation of the KRT17 pathway could potentially convert immunologically “cold” tumors into “hot” ones, thereby expanding the population of CRC patients who might benefit from immunotherapy.^19,20 Additionally, the stage-specific prognostic information provided by KRT17 expression could guide more personalized treatment approaches, particularly in adjuvant therapy decisions for stage II CRC patients.^21,22

Future research directions should focus on elucidating the precise molecular switches that determine KRT17’s contrasting roles in different CRC contexts, developing targeted strategies to manipulate its immune-modulatory functions, and validating its utility as a predictive biomarker in prospective clinical trials of combination immunotherapy regimens.

Esophageal Squamous Cell Carcinoma

KRT17 is significantly upregulated in esophageal squamous cell carcinoma (ESCC), correlating with aggressive tumor characteristics, including advanced clinical stage, invasion depth, lymph node metastasis, and poor prognosis in advanced disease.²³ Mechanistically, KRT17 promotes ESCC cell proliferation, migration, and metastasis by activating AKT signaling and inducing epithelial-mesenchymal transition (EMT), processes known to contribute to chemoresistance in cancers.²⁴ This molecular involvement suggests that KRT17 may play a role in drug resistance, as EMT and AKT pathway activation are frequently linked to evasion of therapy-induced apoptosis and increased tumor survival. Moreover, KRT17 serves as a promising diagnostic biomarker for ESCC detection,²⁵ highlighting its dual potential as a therapeutic target for disrupting tumor progression pathways and overcoming treatment resistance.²⁴

Gastric Cancer

KRT17 critically drives gastric cancer (GC) progression and emerges as a compelling therapeutic target. Functional studies demonstrate that KRT17 depletion exerts broad antitumor activity by suppressing pro-survival AKT/mTOR signaling, thereby inhibiting tumor growth and dissemination.²⁶ Clinically, elevated KRT17 expression is strongly associated with aggressive clinicopathological features, including advanced invasion depth and lymph node metastasis, as well as poorer prognosis. Silencing KRT17 promotes apoptotic cell death and induces G1/S cell-cycle arrest—mechanisms indicative of intrinsic therapeutic resistance.²⁷ Importantly, KRT17 deficiency in diffuse GC triggers cytoskeletal reorganization that activates a KRT17/YAP/IL6 axis, subsequently driving E-cadherin loss and epithelial-mesenchymal transition (EMT), processes fundamentally linked to metastasis and treatment resistance.²⁸ Furthermore, KRT17’s role within TGF-β signaling networks correlates with immunosuppressive microenvironments and holds predictive value for immunotherapy response, highlighting its potential as a target for overcoming treatment resistance.²⁹ Collectively, KRT17 orchestrates diverse oncogenic and resistance-associated pathways in GC, solidifying its candidacy for molecularly targeted therapies.

Head and Neck Cancer

Emerging research identifies KRT17 as a critical mediator of drug resistance and immune evasion in head and neck squamous cell carcinoma (HNSCC), positioning it as a promising therapeutic target. High KRT17 expression is strongly associated with immune evasion and resistance to immune-checkpoint blockade (ICB), as demonstrated in syngeneic mouse models where KRT17-knockout (KO) HNSCC tumors exhibited reduced growth, spontaneous regression, and enhanced CD8+ T-cell infiltration compared to KRT17-expressing tumors. Importantly, KRT17-KO tumors regained sensitivity to ICB, while parental tumors remained resistant.³⁰ Mechanistically, KRT17 expression broadly alters the tumor immune landscape, suppressing antitumor immunity across lymphoid and myeloid cell populations.³⁰ In human HNSCC, elevated KRT17 correlates with poor response to pembrolizumab, underscoring its clinical relevance to immunotherapy resistance.³⁰ Paradoxically, KRT17 also functions as an early differentiation marker in HNSCC tissue. Inducible mucosa-like differentiation, characterized by KRT17 upregulation and cornification, drives the epigenetic loss of malignancy—manifested by proliferation arrest, diminished tumor-initiating capacity, and chromatin reorganization.³¹ This differentiation program, often localized near necrotic areas and triggered by inflammatory signals, intrinsically suppresses malignancy but may coexist with pro-tumorigenic KRT17 functions in stressed microenvironments.³¹ Collectively, KRT17 exhibits dual context-dependent roles: as a stress-induced driver of immunosuppression and ICB resistance, and as an early differentiation marker in terminal cell maturation programs. Its consistent implication in therapy resistance highlights KRT17 as a compelling target for overcoming immune evasion and sensitizing HNSCC to existing immunotherapies.

Lung Cancer

KRT17 overexpression is a significant feature in non-small cell lung cancer (NSCLC), correlating strongly with poor prognosis in both lung adenocarcinoma (LUAD) and lung squamous cell carcinoma (LSCC), particularly predicting worse survival for LUAD patients and associations with poor differentiation and lymphatic metastasis.^32,33 Functionally, KRT17 enhances tumor cell proliferation and invasiveness, primarily by activating the Wnt/β-catenin signaling pathway—leading to upregulation of downstream targets like cyclin D1, c-Myc, and MMP7—and by promoting the epithelial-mesenchymal transition (EMT) process through increased expression of Vimentin, MMP-9, and Snail, alongside decreased E-cadherin expression.³² Furthermore, research identifies alpha-2-macroglobulin like 1 (A2ML1) as a protein highly correlated with KRT17 expression in NSCLC; combined analysis of KRT17 and A2ML1 expression provides enhanced, independent prognostic information beyond standard clinicopathological factors, potentially improving risk stratification for patient management.³³ Due to its critical role in driving aggressive tumor behavior and its robust association with adverse outcomes, KRT17 represents not only a powerful prognostic biomarker but also a compelling candidate for future therapeutic targeting strategies in NSCLC.^32,33

Oral Squamous Cell Carcinoma

KRT17 is consistently overexpressed in oral squamous cell carcinoma (OSCC) tissues and demonstrates significant potential as both a diagnostic biomarker and a therapeutic target. Specifically, KRT17 was found to be upregulated in 100% of OSCC patient samples tested, highlighting its potential role as a diagnostic biomarker.³⁴ Functional studies reveal that KRT17 expression actively promotes the proliferation, migration, and invasion capabilities of OSCC cells, contributing to tumor progression.³⁵ Interestingly, the gain-of-function mutation p53R248W suppresses KRT17 expression, subsequently reducing tumor growth, invasion, and improving survival outcomes in mouse models. This indicates a direct regulatory link between mutant p53 (R248W) and KRT17 downregulation, suggesting that tumors harboring this specific mutation may represent a distinct OSCC subtype with a potentially better prognosis.³⁵ Furthermore, KRT17 has been identified as a key shared oncogenic signature between Oral Lichen Planus (OLP) and OSCC, suggesting it plays a fundamental role in early carcinogenic pathways common to both conditions.³⁶ While direct evidence linking KRT17 to drug resistance in OSCC is not explicitly presented in the provided abstracts, its pivotal role in promoting aggressive tumor phenotypes and its shared expression in precursor lesions underscore its importance as a candidate therapeutic target; modulating KRT17 activity or expression could offer a novel avenue for treating OSCC, particularly in tumors not carrying the suppressive p53R248W mutation. Therefore, KRT17 represents not only a strong diagnostic marker but also a promising focal point for developing future OSCC therapies.

Pancreatic Cancer

KRT17 has emerged as a critically important molecular biomarker and functional mediator in pancreatic ductal adenocarcinoma (PDAC), where it contributes significantly to tumor progression, therapy resistance, and immune microenvironment remodeling. Extensive transcriptomic analyses consistently demonstrate that KRT17 is among the most significantly upregulated genes in PDAC tissues compared to normal pancreatic tissue, positioning it as a central player in pancreatic cancer pathogenesis.³⁷

A defining feature of KRT17 in PDAC is its role in generating intratumoral heterogeneity through the formation of intermediate cellular states. Spatially resolved single-cell analyses reveal that KRT17-expressing cancer cells frequently co-express both basal markers (KRT17, KRT5) and classical markers (GATA6, TFF1), creating a continuous phenotypic spectrum that bridges the conventional basal-like and classical subtypes.³⁸ This heterogeneity is not merely observational but has direct clinical implications, as transcriptome-based classification systems (PurIST) demonstrate that KRT17-high/basal-like subtypes correlate significantly with resistance to FOLFIRINOX chemotherapy and poorer overall survival outcomes.³⁹

The mechanistic basis for KRT17-mediated therapy resistance operates through both cell-autonomous and non-cell-autonomous pathways. Intrinsically, KRT17 drives malignant progression through sustained activation of the FAK/SRC/ERK signaling axis. This pathway activation promotes cancer cell proliferation, invasion, and apoptosis evasion, with KRT17 silencing effectively reversing these effects.⁴⁰ The microRNA miR-485-5p serves as an important upstream regulator of KRT17, and its targeted restoration represents a potential therapeutic strategy to suppress KRT17 expression and sensitize tumors to conventional chemotherapy.⁴⁰

Extrinsically, a distinct KRT17high/CXCL8+ tumor subpopulation secretes multiple cytokines, with CXCL8 being particularly important for recruiting and activating myeloid cells (especially granulocytes) to create an immunosuppressive tumor microenvironment.⁴¹ The abundance of this specific subpopulation correlates with both local immunosuppression and systemic protumorigenic changes, including peripheral blood granulocyte expansion. Clinically, the persistence of this KRT17high/CXCL8⁺ signature following chemotherapy predicts significantly poorer prognosis, suggesting its potential utility as a dynamic biomarker for treatment response monitoring.⁴¹

The translational implications of these findings are substantial. KRT17 expression patterns may guide treatment selection, as patients with KRT17-low/classical tumors derive greater benefit from FOLFIRINOX chemotherapy compared to those with KRT17-high/basal-like tumors.³⁹ From a therapeutic development perspective, multiple targeting strategies show promise: direct KRT17 inhibition (through genetic silencing or pharmacological approaches), restoration of miR-485-5p expression, inhibition of downstream FAK/SRC/ERK signaling, and disruption of CXCL8-mediated myeloid cell recruitment.^40,41 The combination of KRT17 with CXCL8 detection offers particularly strong clinical potential for patient stratification and treatment monitoring.

Future research directions should focus on developing specific KRT17-targeting agents, validating the prognostic and predictive value of KRT17-based classifiers in prospective clinical trials, and exploring rational combination therapies that simultaneously target both the cell-autonomous and microenvironmental functions of KRT17. The multifaceted nature of KRT17’s involvement in PDAC pathogenesis—spanning cellular plasticity, signaling pathway activation, and immune modulation—makes it an exceptionally promising target for addressing the profound therapeutic challenges posed by this devastating malignancy.⁴²

Skin Cancer

KRT17, a stress-induced keratin, plays a significant role in skin tumorigenesis by regulating epithelial differentiation and tissue homeostasis, with its absence often linked to features that may promote drug resistance. For instance, research shows that reduced KRT17 expression is associated with epithelial-to-mesenchymal transition (EMT) and increased levels of cancer stem-like cell markers such as CD271, which are key contributors to resistance phenotypes in malignancies, thereby implicating KRT17 as a potential modulator of skin cancer drug resistance.⁴³ Additionally, computational analyses identify KRT17 as one of the common hub genes in prevalent skin cancers like basal cell carcinoma and actinic keratosis, highlighting its prominence in shared molecular pathways and its viability as a therapeutic target for drug discovery and repurposing strategies.⁴⁴ Consequently, targeting KRT17 or its regulatory network could offer a novel approach to overcoming resistance mechanisms and enhancing treatment efficacy in skin cancers.

Thyroid Cancer

KRT17 is significantly overexpressed in thyroid cancer (TC) tissues and cell lines, playing a critical role in malignant progression.⁴⁵ Mechanistically, the transcription factor TP63 directly binds to the promoter region of KRT17 to upregulate its expression.⁴⁵ This TP63-mediated overexpression of KRT17 activates the AKT signaling pathway, subsequently driving epithelial-mesenchymal transition (EMT)—a key process that enables tumor cell invasion and metastasis.⁴⁵ Functional assays demonstrate that knockdown of TP63 suppresses TC cell proliferation, migration, and invasion, effects that can be rescued by restoring KRT17 expression, confirming KRT17’s downstream role in TP63-driven oncogenicity.⁴⁵ Collectively, these findings establish KRT17 as a pivotal molecular effector in TC progression and highlight its potential as a novel therapeutic target for disrupting the TP63/KRT17/AKT/EMT axis-driven malignancy.⁴⁵

Urothelial Carcinoma

Keratin 17 has emerged as a sensitive biomarker for urothelial carcinoma (UC), demonstrating significant diagnostic value in both cytologic and tissue-based assessments. In urine cytology, KRT17 immunocytochemistry achieves high sensitivity for detecting UC across all grades, with a defined threshold of immunoreactive cells proving optimal for diagnosis.⁴⁶ For upper tract urothelial carcinoma (UTUC), KRT17 immunohistochemistry robustly distinguishes malignant from benign urothelium, showing significantly elevated expression and distinct non-basal localization patterns in invasive and non-invasive tumors compared to normal tissue.^47,48 The full-thickness urothelial staining pattern of KRT17 in biopsies exhibits high reproducibility and superior diagnostic utility compared to CK20/CD44/p53 panels in differentiating UTUC from benign mimics.⁴⁸ Although independent of tumor grade or stage, KRT17’s consistent overexpression in UC underscores its potential as a diagnostic adjunct.^47,48 Given its established role in cell cycle progression and conserved expression in UC pathogenesis,^46,47 KRT17 warrants investigation as a novel therapeutic target for precision interventions in urothelial malignancies.

Conclusion and Outlook

KRT17 has emerged as a pivotal driver of therapy resistance across multiple cancer types, functioning through diverse molecular mechanisms that underscore its significance in oncology (Table 1). Its oncogenic functions are primarily mediated through the activation of key signaling pathways—including AKT/ERK in bladder cancer,^6,7 Wnt/β-catenin in triple-negative breast cancer,¹⁰ and FAK/SRC/ERK in pancreatic cancer⁴⁰—as well as the induction of epithelial-mesenchymal transition (EMT) in cancers such as cervical¹⁴ and bladder⁶ (Figure 3).

Table 1.

Summary of KRT17’s Roles, Mechanisms, and Therapeutic Implications Across Cancers

Cancer Type	KRT17 Expression & Prognostic Correlation	Key Signaling Pathways Involved	Type of Therapy Resistance Mediated	Therapeutic Implications and Potential Strategies	Ref
Bladder Cancer	Overexpressed; correlated with advanced grade/stage and poor prognosis	AKT signaling, ERK signaling	Cisplatin resistance	KRT17 knockdown sensitizes cells to cisplatin; potential target for combination therapy	[6–8]
Triple-Negative Breast Cancer (TNBC)	Overexpressed in TNBC and associated with doxorubicin resistance	Wnt/β-catenin signaling	Doxorubicin resistance	KRT17 knockdown reverses doxorubicin resistance; inhibiting KRT17 could improve chemotherapeutic efficacy	[10]
Cervical Cancer	Overexpressed; associated with paclitaxel resistance and promoted migration	Regulation by lncRNA MIR205HG/SRSF1 axis	Paclitaxel resistance	Berberine inhibits cell viability and metastasis by suppressing KRT17; KRT17 is a potential diagnostic and therapeutic target	[14–17]
Colorectal Cancer (CRC)	Conflicting reports: High expression associated with poor prognosis in stage II/III CRC2743. High expression in tumor buds associated with good prognosis and T-cell infiltration	YTHDF2-CXCL10 axis (promotes T-cell infiltration); Degrades p27 (cell cycle progression)	Not explicitly stated	High KRT17 may predict response to anti-PD-1 immunotherapy; KRT17/p27 combination is a strong prognostic biomarker	[19–22]
Esophageal Squamous Cell Carcinoma (ESCC)	Overexpressed; correlated with advanced stage, metastasis, and poor prognosis	AKT signaling, EMT	Not explicitly stated	KRT17 is a negative prognostic biomarker and a potential therapeutic target for ESCC	[23,24]
Gastric Cancer (GC)	Generally overexpressed; high expression correlates with aggressive features and poor prognosis; In diffuse GC, low expression linked to EMT and poor prognosis	AKT/mTOR, AMPKα1/CREB. YAP/IL6 axis (when KRT17 is low)	Not explicitly stated	KRT17 knockdown inhibits tumor growth and motility; a potential molecular target for therapy	[26–28]
Head and Neck Squamous Cell Carcinoma (HNSCC)	Overexpressed; high levels associated with immune evasion and poor response to immunotherapy	Not specifically defined, but alters broad immune landscape	Resistance to immune-checkpoint blockade (ICB)	KRT17 contributes to an immunologically “cold” tumor; its targeting may overcome ICB resistance	[30]
Non-Small Cell Lung Cancer (NSCLC)	Overexpressed; correlates with poor differentiation, lymphatic metastasis, and poor prognosis	Wnt/β-catenin signaling, EMT	Not explicitly stated	KRT17 is a potential indicator of progression and poor survival; a candidate prognostic biomarker	[32,33]
Oral Squamous Cell Carcinoma (OSCC)	Overexpressed; serves as a diagnostic biomarker	p53 mutation (R248W) suppresses KRT17 to inhibit progression	Not explicitly stated	KRT17 is a potential diagnostic biomarker. p53R248W mutation defines an OSCC subtype with good prognosis	[34,35]
Pancreatic Ductal Adenocarcinoma (PDAC)	Overexpressed; part of a basal-like signature associated with poor prognosis	FAK/SRC/ERK pathway. miRNA-485-5p regulation	Associated with chemotherapy resistance	KRT17 is a prognostic biomarker. Targeting the miRNA-485-5p/KRT17/FAK axis is a potential strategy; Subtyping (eg, PurIST) can predict response to FOLFIRINOX	[37–40]
Thyroid Cancer	Overexpressed; promoted by transcription factor TP63	AKT signaling, EMT	Not explicitly stated	The TP63/KRT17 axis is a potential therapeutic target for inhibiting progression and EMT	[45]

Figure 3.

Mechanistic role of KRT17 involved in drug-resistant tumors.

KRT17 exhibits a complex and context-dependent role in modulating the tumor immune microenvironment (TIME). While it promotes immunosuppression in head and neck cancer³⁰ and pancreatic cancer,⁴¹ it enhances T-cell infiltration and improves response to immune checkpoint inhibitors in colorectal cancer.^19,20 This functional duality—sometimes immune-activating, sometimes immunosuppressive—highlights that KRT17 cannot be categorically defined as solely inhibitory or stimulatory within the TIME. Its effects likely depend on factors such as tumor type, stromal composition, oncogenic drivers, and cytokine milieu, all of which merit further investigation. Additionally, KRT17 contributes broadly to chemotherapy resistance across multiple cancers, including cisplatin resistance in bladder cancer,⁷ doxorubicin resistance in breast cancer,¹⁰ paclitaxel resistance in cervical cancer,¹⁴ and resistance to FOLFIRINOX in pancreatic cancer.³⁹ These mechanisms, combined with its immunomodulatory functions, underscore its central role in therapeutic response. Critically, the paradoxical behavior of KRT17 has profound clinical implications. Its potential as a therapeutic target or predictive biomarker for immunotherapy must be interpreted within specific cancer contexts. A nuanced, disease-specific approach is essential to avoid misinterpretation and to advance personalized treatment strategies aimed at overcoming resistance.

Strategies targeting KRT17, such as genetic silencing or inhibition by compounds like berberine, demonstrate potential for overcoming resistance and improving therapeutic efficacy in preclinical studies. For instance, berberine has been shown to suppress KRT17 expression and reverse its pro-tumor effects in cervical cancer models.¹⁶ However, these approaches face significant limitations that hinder clinical translation. First, there is a critical lack of highly specific, clinical-grade KRT17 inhibitors. Most current research relies on genetic tools (eg, siRNA or shRNA-mediated knockdown) or repurposed compounds like berberine, which were not designed for direct KRT17 targeting. Developing inhibitors that selectively block KRT17’s oncogenic functions while maintaining favorable pharmacokinetic properties remains a major challenge. Second, inherent drawbacks of candidate molecules such as berberine include poor oral bioavailability and rapid metabolism in vivo, which severely limit its clinical utility despite promising preclinical results. Third, KRT17 drives resistance through complex, redundant signaling pathways (eg, AKT/ERK in bladder cancer,^6,7 Wnt/β-catenin in breast cancer,¹⁰ and FAK/SRC/ERK in pancreatic cancer⁴⁰). Targeting KRT17 alone may be insufficient due to compensatory mechanisms within these networks, necessitating rational combination therapies to achieve durable responses. To advance KRT17-targeted strategies into clinical practice, it is essential to develop specific inhibitors of KRT17 or its interacting partners, optimize their drug-like properties, and design pathway-informed combination regimens, followed by rigorous preclinical and clinical studies to evaluate these approaches—either as monotherapy or in combination with chemotherapy or immunotherapy—for safety and efficacy in reversing resistance and enabling successful clinical translation.

Postoperative tumor recurrence primarily arises from residual, aggressive tumor cell subpopulations with inherent therapy-resistant potential, in which KRT17—a key driver of chemoresistance across multiple cancers—is frequently enriched, thereby contributing to adjuvant treatment failure and relapse.⁴⁹ KRT17 promotes resistance through pathways such as AKT/mTOR signaling, which aligns closely with mechanisms underlying postoperative metastasis, while also fostering an immunosuppressive tumor microenvironment via effector molecules like CXCL8, providing a protective niche for residual malignant cells. To counteract KRT17-mediated immunosuppression and chemoresistance, immune cell-derived exosomes have emerged as a promising nanoplatform by leveraging their innate biocompatibility and targeting specificity.⁵⁰ These exosomes can deliver immunomodulatory cargo (eg, miRNAs, cytokines) or engineered targeting moieties to restore T-cell and NK cell cytotoxicity, offering a novel strategy to eliminate residual resistant cells. Such nanotechnology-based delivery systems represent a compelling approach for localized anti-KRT17 therapies aimed at preventing recurrence and improving prognosis.

Future studies should prioritize investigating the molecular mechanisms mediated by KRT17 across various malignancies—such as hepatocellular carcinoma and cholangiocarcinoma—with particular attention to its involvement in DNA damage response and immune regulation. In parallel, KRT17 should be rigorously evaluated as a clinical biomarker to predict treatment sensitivity, resistance, and prognosis, especially in the context of immunotherapy for colorectal cancer. These initiatives will promote personalized oncology by enabling more precise diagnostics and facilitating the development of novel strategies to counter treatment resistance.

Disclosure

The author reports no conflicts of interest in this work.