HMMR in human cancers: regulatory mechanism and biological function.

Background
Hyaluronan (HA) is a linear, water-soluble polysaccharide composed of alternating N-acetylglucosamine and D-glucuronic acid units linked by β-1,4- and β-1,3-glycosidic bonds [1]. As a key component of the extracellular matrix (ECM), HA is primarily localized in soft connective tissues [2] and plays critical roles in various biological processes, including tissue development, inflammation, and cancer progression [3–5]. The biological functions of HA are regulated by its unique physical properties, dynamic turnover, and interactions with specific cell surface receptors [6]. Under physiological conditions, high molecular weight HA ( > 900 kDa) predominates, contributing to tissue homeostasis, anti-inflammatory responses, and wound repair [7].
HA exerts its biological effects by binding to specific cell surface receptors, including Lymphatic Vessel Endothelial Hyaluronan Receptor-1, Cluster of Differentiation 44 (CD44), Hyaluronan-Mediated Motility Receptor (HMMR), Layilin, and Toll-like Receptor 2 [1, 6]. CD44, the most extensively studied HA receptor, is widely expressed in embryonic stem cells, bone marrow, and connective tissues [8, 9]. It also interacts with ligands such as collagen and osteopontin to regulate cell adhesion, migration, and signaling [10, 11]. Notably, CD44 is significantly upregulated in specific cancer subpopulations, particularly those undergoing epithelial-mesenchymal transition (EMT), which enhances invasiveness and chemoresistance, making it a critical tumor biomarker [12, 13].
HMMR (also known as RHAMM, CD168, or IHABP) is another important HA receptor, expressed in a variety of cell types, including fibroblasts, smooth muscle cells, macrophages, and lymphocytes [14]. HMMR preferentially binds to low-molecular weight HA (LMW-HA; < 120–250 kDa), which is often enriched in pathological conditions and correlates with enhanced cell proliferation, motility, inflammation, M1 macrophage polarization, and ECM remodeling [7]. HMMR plays a pivotal role in the progression and poor prognosis of several cancers, including breast cancer [15], head and neck squamous cell carcinoma (HNSCC) [16], and B cell acute lymphoblastic leukemia (ALL) [17]. Elevated HMMR expression is strongly linked to reduced overall survival (OS) in cancer patients [18], highlighting its potential as a prognostic biomarker. At the molecular level, HMMR is regulated by a complex network of transcription factors and signaling pathways, contributing to cancer progression and invasion through multiple oncogenic routes. This review provides a comprehensive summary of the discovery and structural features of HMMR, and elaborates on its functional roles in tumor development and metastasis. It outlines the upstream regulatory mechanisms and downstream signaling pathways involved in oncogenic processes, with particular emphasis on the biological functions and clinical significance of HMMR, advancing our understanding of cancer biology and offering a foundation for developing novel diagnostic, prognostic, and therapeutic strategies targeting the HMMR signaling axis.

The topology of HMMR
Turley et al. first purified and identified an HA-binding protein from chick heart fibroblast cells, which was shown to influence cell adhesion and motility, and was considered a precursor or related protein of HMMR [19]. Subsequent study revealed the distribution patterns of HA and its binding proteins in fibroblasts, suggesting their role in cell motility through interactions with cytoskeletal proteins [20]. In 1992, Hardwick et al. cloned the cDNA of HMMR, predicted to be approximately 58 kDa [21], and identified its association with H-ras regulation. This discovery linked HMMR to cell motility and malignant transformation, positioning it as a key factor in ras-driven tumor progression [21, 22]. Further research confirmed the chromosomal localization of the HMMR gene and suggested its involvement in human diseases, particularly in 5q- associated myeloid disorders [23]. In recent years, significant advances have been made in understanding HMMR, especially in terms of its intracellular distribution and its role as a multifunctional intracellular protein [24]. HMMR has been shown to regulate proper spindle formation [25], promote cell proliferation and migration during central nervous system development [26], and contribute to tumor proliferation, invasion, and associated signaling pathways [27]. Later research has underscored the critical role of HMMR in disease pathogenesis, highlighting its potential as a diagnostic and prognostic biomarker, as well as a therapeutic target, thus opening new avenues for clinical applications [18].
HMMR is a hydrophilic protein with a coiled-coil structure, composed of 725 amino acids, with a molecular weight of approximately 84 kDa. The HMMR gene is located on human chromosome 5 (5q34), consisting of 18 exons and two alternative start codons [21, 23, 28, 31]. Moreover, HMMR generates multiple functionally distinct isoforms through alternative splicing, alternative usage of translation start codons, and post-translational modifications (Fig. 1D) [31]. While expression levels are typically low in normal tissues [32], significant upregulation occurs in pathological conditions, particularly in malignant cells [14, 33]. For example, isoform B has been shown to enhance the phosphorylation of epidermal growth factor receptor (EGFR), extracellular signal-regulated kinase (ERK) 1/2, and signal transducer and activator of transcription 3 (STAT3) in pancreatic neuroendocrine tumors, correlating with liver-specific metastasis and increased sensitivity to EGFR inhibitors [34]. Additionally, three distinct HMMR splice variants, including those involving exons 2–4, were identified in a cervical cancer case recently [35]. Despite their relevance to cancer, the functions of HMMR splice variants remain poorly understood, and the mechanisms underlying their selective expression are still unclear [36]. Future research should focus on elucidating these regulatory mechanisms, defining the biological roles of each isoform in tumor development and progression, and assessing their potential as diagnostic biomarkers or therapeutic targets in cancer treatment.
The C-terminal region of HMMR plays a critical role in cytoskeletal regulation and signal transduction. This region comprises a 35-amino acid segment [28], containing two canonical basic motifs, designated as Basic (B)(X)7 Basic (B(X7)B), where B represents lysine or arginine, and X denotes non-acidic residues (Fig. 1C) [28, 37]. Truncation and mutational analyses have identified this domain as a critical binding site for HA [38]. The basic residues within the B(X7)B motifs enhance HA binding affinity by forming salt bridges with glucuronic acid moieties, while hydrophobic residues further stabilize the interaction by displacing interfacial water and HA itself may undergo conformational changes to accommodate the HMMR binding site [39]. Further study demonstrates that the B(X7)B motif can confer significant HA-binding capacity through different spatial arrangements, while under specific conditions it undergoes conformational changes and self-assembles into nanofibers with enhanced binding [40]. Such findings underscore the structural significance of the B(X7)B motif in HA recognition and point to its potential role in fine-tuning molecular affinity. The HA/HMMR interaction is involved in a variety of physiological and pathological processes, including the regulation of cell migration [21], promotion of inflammatory cytokine expression, contribution to fibrosis [41], modulation of macrophage behavior [41, 42], and support of tumor cell transformation and survival [22, 43]. Consequently, peptide mimics that block HA/HMMR binding have been shown to inhibit tumor cell migration and invasion, reduce inflammatory signaling, and demonstrate therapeutic potential for treating cancer [39, 44].
Additionally, the B(X7)B motifs substantially overlap with the basic leucine zipper (bZIP) domain of HMMR, which is essential during mitosis. This region exhibits high sequence similarity to the C-terminal domain of Xklp2, a known spindle regulator, suggesting a conserved mechanism for microtubule binding and regulation [45]. Xklp2 employs its C-terminal leucine zipper (LZ) domain to interact with targeting protein for Xklp2 (TPX2) and the dynein/dynactin motor complex, facilitating its localization to the centrosome and spindle poles. Through these interactions, Xklp2 coordinates centrosome separation, spindle assembly, and pole stabilization, ensuring proper bipolar spindle formation during mitosis [45, 46]. Similarly, HMMR interacts with TPX2 via its C-terminal bZIP domain, targeting it to spindle assembly sites through a dynein-dependent mechanism. This interaction stabilizes and spatially organizes TPX2, facilitates Aurora kinase A (AURKA) activation, and ensures proper mitotic spindle assembly [47]. Furthermore, HMMR promotes the formation of an inhibitory TPX2/Eg5 complex at spindle poles, dampening Eg5-driven outward forces and maintaining spindle force balance. Loss of HMMR disrupts TPX2 localization and compromises spindle integrity, resulting in chromosome misalignment, spindle rotation defects, and chromosomal scattering [48]. Additionally, the bZIP domain of HMMR is predicted to form a stable coiled-coil structure with LZ characteristics, suggesting its capacity for dimerization, which may enhance transcriptional interactions and HA-binding affinity by stabilizing its conformation [36]. Beyond its functional roles, the bZIP domain of HMMR is evolutionarily conserved across vertebrates and serves as a hallmark for identifying HMMR orthologs. However, homologous bZIP-like motifs have also been identified in invertebrates that do not synthesize HA, indicating that the bZIP domain of HMMR may have originally evolved to facilitate protein–protein interactions, with its subsequent adaptation for HA-mediated signaling representing a functional expansion in vertebrate evolution [36, 49].
HMMR contains two distinct microtubule-binding domains, one located within C-terminal basic domain and another identified in the N-terminal region [25]. The N-terminal globular domain, encoded by exon 4 and enriched with basic residues, likely binds microtubules through electrostatic interactions, promoting microtubule stabilization and HMMR‘s colocalization with the microtubule network during interphase [25, 45]. Upon binding to microtubules, HMMR forms a spindle-localized complex with FAM83D through a central coiled-coil domain spanning amino acids 365–546 [50]. This complex facilitates the recruitment of CK1α to the mitotic spindle via FAM83D, establishing a regulatory axis with dynein light chain 1 that ensures proper spindle orientation and alignment of the cell division axis during mitosis [51]. When the N-terminal domain of HMMR is deleted, the protein retains the ability to bind microtubules through its C-terminal domain. However, this truncated form is unable to fully regulate microtubule dynamics or maintain mitotic fidelity [52]. The loss of the N-terminal domain results in a failure to prevent multipolar spindle formation or ensure accurate chromosome alignment. Additionally, the truncated form exhibits altered localization, with diffuse cytoplasmic and nuclear distribution due to disrupted association with interphase microtubules [45, 52]. These findings emphasize the critical role of HMMR in mitotic regulation, highlighting its coordinated interactions with microtubules and spindle-associated proteins to guarantee precise chromosome segregation and spindle orientation during cell division.

The regulation of HMMR in cancers
The expression of HMMR is tightly regulated by multiple upstream signaling pathways and transcription factors, positioning it as a critical hub within oncogenic regulatory networks (Fig. 2). Aberrant activation of HMMR has been implicated in promoting migration, invasion, and metastasis across a variety of cancers. Exogenous HA, a major ECM component, has been shown to upregulate HMMR expression in breast cancer cells in a concentration-dependent manner [53]. Mechanistically, HA binds to the cell surface receptor CD44 and activates the downstream protein kinase Cδ (PKCδ)/Rac1/c-Jun N-terminal kinase (JNK) signaling pathway. This leads to enhanced expression and activation of the AP-1 transcription factor complex, which directly binds to the HMMR promoter, driving its transcription and upregulating HMMR expression [54, 55]. The HA/CD44 complex also activates the EGFR/ERK pathway, which correlates with the activity of the transcription factor E2F1. E2F1 directly binds to the HMMR promoter to further enhance transcription. HMMR, in turn, acts as a co-activator of E2F1, reinforcing its activation of downstream targets such as fibronectin (FN). This feedback loop amplifies E2F1 signaling, promoting integrin-β1/focal adhesion kinase (FAK) signaling, cytoskeletal remodeling, and tumor cell motility [43, 56]. Inhibition of HA synthases HAS2/3 downregulates CD44 and HMMR expression, leading to apoptosis in tumor cells [43]. Transforming growth factor β (TGF-β) also significantly upregulates HMMR and promotes its membrane localization [57, 58]. TGF-β activates SMAD3, which cooperates with the Yes-associated protein (YAP)1/TEA domain family member (TEAD) complex to induce HMMR expression. Simultaneously, TGF-β enhances nuclear factor-κB (NF-κB) signaling via p65 activation, contributing to elevated HMMR levels [59, 60]. Notably, YAP acts as a key integrator of the non-canonical mevalonate/Hippo pathway, bypassing the canonical Hippo signaling pathway. This pathway relies on geranylgeranyl pyrophosphate-mediated Ras homolog (Rho) GTPase activation, promoting YAP nuclear translocation and enhancing breast cancer cell migration and invasion [61]. Simvastatin, a mevalonate pathway inhibitor, suppresses Rho-mediated YAP nuclear localization and transcriptional activity, leading to a marked reduction in HMMR expression and ERK phosphorylation in breast cancer cells [61].
In prostate cancer, HMMR expression is regulated by the androgen receptor (AR) through transcriptional control and protein–protein interactions [62]. In androgen-dependent cells, dihydrotestosterone (DHT)-activated AR significantly upregulates HMMR mRNA and protein levels through the phosphoinositide 3-kinase (PI3K)/protein kinase B (Akt)/mammalian target of rapamycin (mTOR) signaling pathway. This pathway enhances the activity of the transcription factor SRF, which promotes HMMR transcription by binding to its promoter, particularly within the first intron [63]. The use of mTOR inhibitors, such as rapamycin and Torin2, effectively blocks DHT-induced HMMR upregulation, confirming the role of the AR/mTOR/SRF axis in regulating HMMR expression [63]. In the absence of DHT, AR binds directly to HMMR, masking its binding domain and preventing downstream Ras homolog family member A (RhoA)/rho-associated coiled-coil containing protein kinase (ROCK) signaling. Upon DHT stimulation, AR dissociates from HMMR, enabling it to respond to HA and activate the ROCK–PI3K–Akt/mTOR/eIF4E axis, which promotes prostate cancer cell proliferation, migration, and metastasis [62].
p53 and retinoblastoma protein (RB) are well-established tumor suppressors that negatively regulate HMMR expression. Promoter truncation and mutational analyses have demonstrated that p53 suppresses HMMR transcription through a non-canonical mechanism involving the first exon and intron of its promoter, rather than the classical p53-binding elements. Upon activation, p53 downregulates HMMR mRNA and protein levels, thereby contributing to cell cycle arrest and tumor suppression [64]. Recent evidence further indicates that the loss or dysfunction of p53 leads to elevated HMMR expression, significantly promoting the progression of pancreatic intraepithelial neoplasia to invasive pancreatic ductal adenocarcinoma, enhancing tumor invasiveness and metastatic potential, and correlating with poor clinical outcomes [65]. These findings suggest that p53 may normally suppress HMMR expression to counteract its oncogenic activity. Functional RB/E2F binding sites have also been identified in the HMMR promoter. RB represses HMMR transcription by binding to and inhibiting E2F activity. The loss or inactivation of RB releases E2F1/2, thereby increasing HMMR expression, promoting cytoskeletal remodeling, and enhancing metastatic behavior [66]. The loss of both p53 and RB leads to the upregulation of FoxM1 [67]. A recent study in bladder cancer supports this conclusion, showing that p53 and RB loss contributes to FOXM1 upregulation, which further enhances HMMR expression and activates the canonical Wnt/β-catenin signaling pathway, promoting cell proliferation and inducing EMT [68]. Furthermore, in adipocyte-associated endometrial cancer, leptin and visfatin secreted by adipocytes promote SIRT1 expression and deacetylase activity, enhancing FOXM1-driven transcriptional activation of HMMR in a SIRT1-dependent manner [69].
HMMR is targeted for degradation by the anaphase-promoting complex/cyclosome (APC/C) through recognition of multiple conserved degron motifs (D-box, KEN-box, TEK-box) in its C-terminal region, resulting in K11-linked polyubiquitination and subsequent proteasomal degradation [70]. Unlike other Ran-dependent spindle assembly factors such as HURP and NuSAP, which require RanGTP-mediated release from importin-β for APC/C recognition, HMMR is directly degraded by APC/C [70]. Additionally, HMMR is a target of the BRCA1–BARD1 E3 ubiquitin ligase complex, suggesting that its mitotic function may be modulated by BRCA1 activity [71]. Moreover, HMMR expression is also regulated by microRNAs (miRNAs). In clear cell renal cell carcinoma (ccRCC), miR-9-5p directly binds to the 3’-UTR of HMMR, suppressing its expression and inhibiting tumor cell proliferation and migration [72]. Furthermore, long non-coding RNAs (lncRNAs) can act as competing endogenous RNAs, sequestering miRNAs and alleviating their inhibitory effects on target genes. For instance, in lung adenocarcinoma (LUAD), LINC00665 sponges let-7c-5p to relieve its repression of HMMR, promoting glycolysis and tumor cell proliferation [73]. These findings highlight HMMR as a downstream effector in the lncRNA–miRNA–mRNA axis driving tumor progression (Table 1).

HMMR and cancers

HMMR and head and neck cancer
HNSCC encompasses a group of highly aggressive malignancies characterized by complex genetic alterations, primarily affecting the oral cavity, pharynx, nasal cavity, and salivary glands [81]. It ranks as the sixth most common cancer globally [82]. Despite significant advances in immunotherapy in recent years [83], HNSCC continues to show poor outcomes due to late diagnosis, anatomical complexity, and tumor heterogeneity [84], with a 5-year survival rate of just 40–50% [85]. These challenges underscore the urgent need for novel biomarkers and therapeutic targets to improve patient outcomes.
HMMR is significantly upregulated in oral squamous cell carcinoma (OSCC), with its elevated expression strongly correlating with advanced TNM staging [86]. Notably, in early-stage OSCC, higher HMMR expression is associated with increased tumor proliferative capacity and poorer survival outcomes, making it a promising prognostic biomarker for risk stratification and therapeutic decision-making [87]. HMMR binds HA and collaborates with CD44 at the cell surface to activate the mitogen-activated protein kinase (MAPK)/ERK signaling pathway, which contributes to cancer cell motility and self-renewal. This pathway facilitates cytoskeletal reorganization, promoting cell migration and proliferation [88]. Additionally, HA/HMMR complexes interact with growth factor receptors, such as platelet-derived growth factor receptors and EGFR, enhancing downstream signaling cascades, sustaining ERK phosphorylation, and driving the expression of mitogenic genes. This process facilitates tumor cell proliferation and motility through the promotion of oncogenic transcriptional programs and cell cycle progression [89]. These findings highlight HMMR‘s pivotal role in regulating multiple oncogenic signaling pathways and its functional importance in the pathogenesis of HNSCC. Further evidence suggests a synergistic relationship between HMMR and TPX2. In salivary gland cancers, particularly adenoid cystic carcinoma, TPX2 expression is significantly elevated compared to normal glandular tissue and may promote abnormal proliferation through the activation of the AURKA-dependent spindle assembly pathway [90]. Moreover, TPX2 expression correlates strongly with that of HMMR, indicating potential cooperation in tumor progression. Similarly, both HMMR and TPX2 are highly expressed in OSCC, and their positive correlation further supports a cooperative oncogenic role in this context [91]. Recent bioinformatic analyses in OSCC have demonstrated that high HMMR expression is significantly associated with advanced clinical stage and poor OS in HNSCC patients [92]. These findings establish HMMR as an independent prognostic marker and a potential tool for risk stratification and personalized patient management.
Recent studies have highlighted the growing importance of immunotherapy, particularly programmed cell death protein (PD-1) and programmed death ligand 1 (PD-L1) inhibitors, in cancer treatment. Compared to traditional chemotherapy, immunotherapy not only extends patient survival but also helps preserve quality of life to a certain extent [93, 94]. While PD-1/PD-L1 immune checkpoint inhibitors have shown remarkable efficacy in recurrent/metastatic HNSCC, their administration is unavoidably associated with immune-related adverse events, including common manifestations such as dermatitis, thyroiditis, and colitis, as well as rare events like hearing loss [95, 96]. Moreover, recent research has indicated that durable responses are observed in only 15–20% of patients. This limited effectiveness is closely linked to multiple immunosuppressive mechanisms within the tumor microenvironment (TME) [97]. HMMR plays a pivotal role in shaping an immunosuppressive TME. In HNSCC, high HMMR expression is strongly associated with increased infiltration of immunosuppressive M2 macrophages, which inhibit antitumor immune responses and contribute to immune evasion, TME remodeling, and poor clinical outcomes [16, 98]. Moreover, HMMR expression correlates positively with key immunosuppressive molecules such as PD-L1, CMTM6, and B7–H4, suggesting its role in facilitating tumor immune evasion [99]. Beyond its immunomodulatory functions, HMMR is also closely linked to the maintenance of cancer stem cell (CSC) properties. Mechanistically, HMMR prevents GSK3β inactivation by inhibiting its phosphorylation, thereby sustaining CSC self-renewal and inhibiting differentiation [88]. HMMR expression positively correlates with CSC markers CD44 and CD133, as well as the EMT-related transcription factor Slug, supporting its role in promoting stem-like traits and EMT [99]. In summary, HMMR plays a dual role in tumor immune evasion and CSC maintenance, marking it as a key factor in immune suppression. These functions not only drive tumor growth and metastasis but also significantly reduce patient survival. As such, HMMR serves as a valuable biomarker for assessing prognosis in HNSCC patients and presents a promising strategy for personalized therapy by targeting both the immunosuppressive TME and CSC.

HMMR and breast cancer
Breast cancer is the most prevalent malignancy among women globally, accounting for approximately one-third of all female cancer cases and responsible for about 15% of cancer-related deaths [100]. While early detection and advancements in systemic therapies have increased the five-year relative survival rate of breast cancer to over 90% in developed countries [85, 101], it remains a significant global health challenge. Epidemiological studies have shown that breast cancer incidence is higher in developed countries due to socioeconomic and lifestyle factors [102], whereas developing regions are experiencing a growing case burden driven by population expansion and the increasing adoption of Western lifestyles [103]. By 2050, the global annual death toll is projected to reach 10.5 million [104]. Moreover, current clinical risk stratification primarily relies on pathological parameters, which often lack precision [101], and patients frequently develop resistance to commonly used clinical inhibitors [105], posing a major clinical challenge in the management of advanced disease. Consequently, there is a pressing need for reliable molecular biomarkers to enhance risk classification and guide personalized treatment. Among these, HMMR has emerged as a promising biomarker and potential therapeutic target in breast cancer.
Breast cancer is a heterogeneous disease, characterized by distinct subtypes. Approximately 10% of breast cancer cases are linked to genetic susceptibility or family history, with BRCA gene mutations being the most common germline mutations associated with breast cancer [106, 107]. HMMR is tightly regulated throughout the cell cycle, with its expression peaking during the G2/M transition and early mitosis [108]. As a critical regulator of mitosis, HMMR is essential for maintaining the expression levels of Cdc2 and Cyclin B1. Suppression of HMMR leads to G2/M arrest, indicating its role in mitotic progression [109]. During mitosis, HMMR not only acts as a substrate for the ubiquitin ligase but also undergoes modulation through BRCA1/BARD1-mediated ubiquitination [71]. By attenuating hyperactive HMMR function, the BRCA1/BARD1 complex ensures the proper localization of TPX2 at spindle poles downstream of the Ran-GTP pathway, thereby maintaining spindle integrity and promoting accurate chromosome segregation [74]. The loss of BRCA1 results in sustained activity of HMMR, disrupting the cortical polarity distribution of the NUMA-dynein complex. This disturbance impairs mitotic spindle orientation, leading to loss of polarity in daughter cells, chromosomal aneuploidy, and depletion of the luminal phenotype. These defects manifest as polyploidy, micronuclei formation, disorganized acinar structures, lumen loss, and aberrant cell alignment. Furthermore, increased reliance on centrosome-dependent microtubule organization exacerbates polarity imbalance, inhibits cell differentiation, and drives the initiation and progression of breast cancer, particularly basal-like breast cancer [75, 110]. In the context of BRCA1 deficiency, overexpression of HMMR induces genomic instability and micronuclei formation, thereby activating the cyclic GMP-AMP synthase (cGAS)/stimulator of interferon genes (STING) pathway. This activation amplifies non-canonical NF-κB signaling, promoting EMT, increased angiogenesis, immune cell infiltration, and downregulation of Claudin-1/3. These tumor phenotypes closely resemble the molecular and histopathological features of human claudin-low and basal-like subtypes of triple-negative breast cancer [111]. Moreover, in breast cancer, AURKA has been identified as a high-risk gene through network modeling and is frequently mislocalized alongside HMMR in BRCA1-deficient cells, both of which promote centrosome abnormalities and genomic instability [71]. Further studies have demonstrated that AURKA phosphorylates and inhibits BRCA1 E3 ubiquitin ligase activity, thereby attenuating BRCA1-mediated suppression of centrosome-dependent microtubule nucleation, ultimately leading to centrosome dysfunction [112].
In addition to regulating cell proliferation and mitosis, HMMR overexpression in breast cancer has been strongly associated with increased extracellular migration and invasion. Studies have shown that HMMR expression is significantly higher in metastatic lesions than in primary tumors, with expression levels positively correlating with tumor grade [113]. Similarly, in vitro studies indicate that invasive breast cancer cell lines exhibit elevated HMMR expression compared to non-invasive counterparts [114]. This enhanced migratory capacity appears to be mediated by an HA-dependent autocrine mechanism, where HMMR and CD44 cooperate at the cell membrane to form signaling complexes. These complexes bind endogenous HA, activating the ERK1/2 signaling pathway, thereby sustaining high basal motility [114]. Further studies reveal that when CD44 expression is reduced, HMMR is upregulated in response to matrix-bound HA, thereby compensating for the loss of CD44 and sustaining ERK1/2 activation. [115]. Knockout of HMMR significantly impairs the invasive capacity and anchorage-independent growth of breast cancer cells, indicating its critical role in driving invasive phenotypes and contributing to the formation of an invasive TME [15]. Additionally, the Hippo pathway plays a pivotal regulatory role in breast cancer initiation and progression, primarily through its downstream effector YAP. Upon translocation to the nucleus, YAP interacts with transcription factors TEAD to directly induce HMMR expression, which in turn promotes ERK activation, facilitating cancer cell migration and invasion [61, 116]. Moreover, YAP1 cooperates with phosphorylated SMAD3, a downstream effector of the TGFβ signaling pathway, potentially engaging TEAD family transcription factors to coordinate HMMR expression, further contributing to tumor cell proliferation, migration, and metastasis [59].
HMMR plays a central role in breast cancer, not only regulating the cell cycle but also promoting tumor cell invasion and metastasis through interactions with various signaling pathways. Bioinformatics analyses have identified high HMMR expression as a potential prognostic biomarker in breast cancer. Patients with elevated HMMR levels exhibit significantly shorter OS and relapse-free survival compared to those with lower expression, with a strong association with poor clinical outcomes [117, 118]. Recent in silico studies have shown that small-molecule inhibitors such as Rapamycin and Torin2 can stably bind to HMMR, demonstrating favorable binding stability and potential inhibitory activity, offering a theoretical foundation for small-molecule therapeutic strategies targeting HMMR in breast cancer [119]. In addition, epirubicin, a widely used chemotherapeutic agent in breast cancer, has been predicted as a drug interacting with HMMR [120]. Overexpression of HMMR confers epirubicin resistance through enhanced proliferative and migratory capacities, elevated CSC properties, and induction of EMT, while its knockdown markedly reduces these resistance-associated phenotypes [121]. Collectively, these findings emphasize the dual function of HMMR as both a molecular biomarker of disease progression and a therapeutic target, highlighting its substantial potential for clinical translation in breast cancer.

HMMR and lung cancer
Lung cancer ranks as one of the most common cancers globally and remains the leading cause of cancer-related deaths, accounting for approximately 1.8 million deaths, or nearly 20% of all cancer fatalities [102]. Significant progress has been made in treating non-small cell lung cancer (NSCLC), with advancements shifting from traditional chemotherapy to targeted therapies that address specific molecular subtypes of LUAD and lung squamous cell carcinoma (LUSC) [122]. However, the tumor heterogeneity and complex gene mutations in NSCLC continue to challenge the application of targeted therapies [123, 124]. This is especially evident in LUSC, where a considerable proportion of patients experience limited or no durable benefit from first-line immune checkpoint inhibitors [125]. Consequently, there is a critical need for novel biomarkers that can better stratify patients and guide more effective therapeutic strategies. HMMR, a multifunctional protein, has emerged as a promising candidate, recognized for its role in tumor progression and immune modulation.
HMMR plays a central role in NSCLC progression by mediating HA-dependent interactions with the ECM, enhancing the activation of the PI3K/AKT and MAPK/ERK signaling pathways. These pathways are essential regulators of tumor cell proliferation, survival, and metastasis [126]. Recent studies have further demonstrated that high HMMR expression promotes tumor cell migration and invasion through direct interaction with MAP4K4, which activates the JNK/c-JUN signaling pathway and upregulates MMP1 expression [127]. Knockdown of HMMR significantly reduces HA synthesis, inhibits EGFR phosphorylation, and suppresses the downstream activation of AKT and ERK pathways, leading to reduced cell proliferation and increased apoptosis [43]. Natural compounds such as emodin and triptolide have been shown to inhibit NSCLC progression by downregulating HA synthase expression and disrupting HA-dependent HMMR signaling. These effects disrupt cell cycle progression by reducing Cyclin A/B levels, induce G0/G1 phase arrest, and enhance apoptosis [128, 129]. HMMR is generally considered an oncogenic factor in NSCLC, with its overexpression linked to increased tumor aggressiveness and poor prognosis. Bioinformatics analyses suggest that HMMR holds potential as a biomarker in NSCLC, particularly in LUAD, where its expression is significantly elevated. High HMMR levels correlate with poorer OS and progression-free survival (PFS) [130], as well as with adverse clinical features, including advanced TNM stage, postoperative residual tumor, poor initial treatment response, and a history of smoking [131]. Notably, in early LUAD patients, high HMMR expression, as part of a gene prognostic signature, helps identify individuals at high risk of recurrence, providing valuable insights for adjuvant chemotherapy decisions [132]. Furthermore, elevated HMMR expression is associated with poor prognosis in other NSCLC subtypes, including large cell carcinoma and LUSC [133, 134]. Collectively, these findings indicate that HMMR plays a pivotal role in NSCLC progression through HA-mediated signaling and positions it as a promising prognostic biomarker and therapeutic target.
Surprisingly, HMMR deficiency in breast cancer mouse models results in significantly increased lung metastasis by impairing STING-dependent DNA damage sensing and suppressing the downstream STING/interferon (IFN)/STAT1 pathway, which dampens immune response activation [135]. In the lung microenvironment, enriched with reactive oxygen species (ROS) and TGF-β, HMMR-deficient tumor cells exhibit enhanced resistance to STING-induced programmed cell death, thereby evading immune surveillance and gaining clonal expansion advantages [135]. Rhosin, a small-molecule inhibitor targeting RhoA/C activity, significantly reduces lung metastases in breast cancer by blocking the RhoA/C-YAP signaling axis and downregulating HMMR [136]. These findings indicate that HMMR plays a critical role in regulating tumor immunity and lung metastasis. Further studies have shown that elevated HMMR expression in LUAD is associated with reduced CD4+ T and NK cell infiltration, increased expression of immune checkpoint molecules, higher TIDE scores, lower IPS scores, and greater infiltration of tumor-associated macrophages. Collectively, these factors point to HMMR‘s role in promoting an immunosuppressive TME, facilitating immune evasion, and contributing to resistance to immunotherapy [137, 138]. Additionally, resveratrol suppresses HMMR expression, enhances CD8+ T cell cytotoxicity, remodels the immune microenvironment, and activates ferroptosis pathways, all of which contribute to a more robust antitumor immune response [139]. Overall, HMMR drives tumor progression through HA-mediated signaling, and its elevated expression is strongly associated with poor prognosis, immunotherapy resistance, and adverse clinical features, highlighting its potential as a biomarker for prognostic evaluation, risk stratification, and therapeutic targeting.

HMMR and other cancers
Prostate cancer is one of the most common solid malignancies in men and remains the second leading cause of cancer-related death in this population [85]. Despite the clinical benefits of AR signaling inhibitors, resistance to these therapies continues to present a significant clinical challenge in prostate cancer [140]. AR signaling inhibitors fail to fully suppress all AR-regulated genes, leaving residual signaling that supports tumor survival [141]. Among these, HMMR has gained attention for its progressive upregulation under androgen deprivation therapy (ADT) and its potential role in driving therapeutic resistance. HMMR is undetectable in normal prostate tissue, benign prostatic hyperplasia, and untreated prostate cancer, but is significantly upregulated following ADT, especially in castration-resistant prostate cancer [142]. HMMR expression progressively increases with the duration of ADT and has been implicated in the development of hormonal resistance. Both clinical and bioinformatic studies have identified HMMR as a promising prognostic biomarker, with elevated expression predicting shorter biochemical recurrence-free survival and a higher risk of disease progression following prostatectomy [142–144]. Under normal AR regulation, HMMR expression and downstream activation are suppressed. However, AR dysfunction leads to HMMR overexpression, which activates the RhoA/ROK1 pathway and subsequently stimulates the PI3K/Akt and mTORC1/eIF4E signaling axes, promoting cancer proliferation, invasion, and metastasis [62]. HMMR also exhibits synergistic or parallel interactions with EGFR-mediated PI3K signaling, contributing to resistance to EGFR-targeted therapies in some patients, highlighting its role in tumor recurrence and therapeutic resistance [145]. More recently, high HMMR expression has been shown to stabilize AURK A by preventing its ubiquitin-mediated degradation, thereby activating the mTORC2/AKT pathway. Activated AKT induces the transcription factor E2F1, which enhances HMMR transcription, establishing a self-reinforcing AURK A/mTORC2/E2F1 feedback loop that drives prostate cancer progression [27]. Collectively, these findings underscore the critical role of HMMR in the initiation and progression of prostate cancer, supporting its potential as a therapeutic target. Targeted inhibition of HMMR has been shown to effectively suppress the proliferation of both androgen-dependent and -independent prostate cancer cells [146]. Additionally, HMMR is closely involved in microtubule regulation, and its inhibition impairs AR nuclear translocation, attenuating AR signaling and downregulating the expression of downstream genes such as prostate-specific antigen [147]. Recent findings suggest that baicalein can inhibit AR expression at the transcriptional level, blocking androgen signaling. Furthermore, by suppressing mTOR expression, baicalein impairs the activation of transcription factors, including SRF, Egr-1, and E2F3α, leading to the downregulation of HMMR transcription and ultimately resulting in significant inhibition of tumor cell growth and migration [148].
HMMR is widely overexpressed in various hematologic malignancies, including multiple forms of leukemia and multiple myeloma (MM) [149, 150]. In chronic lymphocytic leukemia (CLL), HMMR expression correlates positively with disease stage and is significantly upregulated in highly proliferative regions such as the bone marrow and lymph nodes, showing co-localization with the proliferation marker Ki-67 [151]. Elevated HMMR levels are also strongly associated with high-risk genetic abnormalities in CLL, such as unmutated IgVH status, del11q, and del17p, and serve as a predictor of shortened treatment-free survival (TFS) [151]. In chronic myeloid leukemia, HMMR is co-expressed with centrosomal proteins like AURKA, PLK1, and ESPL1, all of which regulate mitotic processes. A delayed decline of these genes during imatinib treatment is linked to poor treatment response and reduced OS [152]. The HMMR gene is highly expressed in patients with MM and is closely associated with the proliferative activity of malignant plasma cells. Its expression correlates significantly with inferior event-free survival and OS, establishing it as an independent molecular marker of poor prognosis [153]. Additionally, an alternatively spliced variant of HMMR, lacking exon 4, is frequently upregulated in MM. This variant lacks the microtubule-binding domain, disrupting cytoskeletal regulation, causing mitotic errors, chromosomal instability, and enhancing tumor aggressiveness [154]. The abnormal enrichment of this variant, V3, is driven by the sustained upregulation of splicing factors PTBP1 and PTBP2, which bind to polypyrimidine tracts within intron 3 of HMMR, promoting exon 4 skipping [155]. In pediatric ALL, HMMR is also highly expressed and closely associated with poor survival, highlighting its potential as both a prognostic biomarker and therapeutic target [17]. Given its frequently overexpression and antigenicity in hematologic malignancies, HMMR has emerged as a promising target for immunotherapy. HMMR-derived peptides are specifically recognized by HLA-A2-restricted CD8+ T cells, eliciting cytotoxic immune responses [156], and have been shown to induce humoral immune responses in a subset of leukemia patients [157]. Notably, HMMR-R3 peptide vaccines have demonstrated the capacity to elicit HMMR-specific CD8+ T cell responses in clinical studies of acute myeloid leukemia and MM. These responses were characterized by increased secretion of IFN-γ and granzyme B, reductions in bone marrow blasts, improvements in peripheral blood parameters, and decreased serum free light chain levels. Notably, these immune responses were in some cases accompanied by a reduction in regulatory T cells, suggesting that HMMR-targeted vaccination may enhance antitumor immunity by alleviating immunosuppressive elements within the TME [158, 159].

Signaling pathways regulated by HMMR in cancer
HMMR is a key regulator of tumor proliferation and progression. As a key integrator of ECM signals, it modulates various malignant behaviors through several interconnected signaling pathways, particularly the MAPK/ERK, TGF-β, and PI3K/AKT pathways (Fig. 3).

HMMR and MAPK/ERK signaling pathway
The MAPK/ERK signaling pathway plays a pivotal role in regulating essential cellular processes such as proliferation, differentiation, survival, and migration. Aberrant activation of this pathway is strongly linked to the initiation and progression of various cancers [160]. HMMR can activate the downstream Ras/MAPK/ERK cascade by binding to HA and cooperating with CD44 or other receptors. This activation promotes the phosphorylation of the ERK pathway, facilitating cell cycle progression and enhancing tumor cell proliferation [89]. In the autocrine mechanism mediated by HA, HMMR on the cell surface forms a complex with CD44 to sustain the activation of the ERK1/2 signaling pathway, collectively promoting elevated basal motility in invasive breast cancer cells [114]. In fibrosarcoma, LMW-HA activates ERK1/2 through HMMR, leading to the phosphorylation of FAK and establishing a HMMR-ERK1/2-FAK axis. This pathway enhances FAK activation, promoting focal adhesion assembly, cytoskeletal reorganization, and increased cell motility [161]. Given its role in tumor invasion, HMMR‘s regulation of the MAPK/ERK pathway positions it as a potential therapeutic target for inhibiting malignant tumor progression.

HMMR and TGF-β signaling pathway
The TGF-β signaling pathway has a dual role in regulating cell proliferation, differentiation, apoptosis, and EMT. It can act as a tumor suppressor in early carcinogenesis but promotes invasion and metastasis in advanced stages of cancer [162]. In gastric cancer, HMMR is highly upregulated in 5-fluorouracil–resistant tissues and cells, where it activates the TGF-β/Smad2 pathway by promoting Smad2 phosphorylation and nuclear translocation. This activation drives EMT and the acquisition of CSC characteristics, leading to poor prognosis and tumor recurrence [163]. Moreover, in fibrosarcoma cells, the HMMR/HA interaction is essential for TGF-β1-induced cell motility. Blocking this interaction with anti-HMMR antibodies or HA-binding peptides significantly reduces cell movement, highlighting HMMR‘s role in tumor migration and metastasis [57].

HMMR and PI3K/AKT signaling pathway
The PI3K/AKT signaling pathway is essential for regulating cell growth, metabolism, and apoptosis resistance, with dysregulated activation commonly observed in various cancers [164]. HMMR collaborates with CD44 to mediate the biological effects of HA. The HA interacts with CD44 and HMMR interaction activates the PI3K/AKT pathway, promoting cell survival, proliferation, migration, invasion, and resistance to apoptosis. This activation contributes to chemoresistance by upregulating ATP-binding cassette transporters, enhancing drug efflux, and facilitating EMT and CSC properties [165]. Additionally, during prostate cancer progression, sulfated HA exerts significant antitumor effects by inhibiting hyaluronidase activity and the HMMR/PI3K/AKT signaling axis, inducing apoptosis, inhibiting invasion, and suppressing angiogenesis [166]. These data indicate that HMMR is a key regulator in the PI3K/AKT pathway. Moreover, HMMR‘s biological functions extend beyond isolated pathway activation. In choriocarcinoma, HMMR facilitates ERK activation and contributes to PI3K-dependent signaling, suggesting a potential crosstalk between the PI3K and MAPK/ERK pathways to promote HA-induced cell migration. This highlights HMMR as a critical signaling hub that integrates multiple oncogenic pathways, thereby amplifying malignant cell migration and invasive potential [167].

HMMR and cGAS/STING signaling pathway
The cGAS/STING pathway is a key component of the innate immune system, responsible for sensing cytosolic DNA and initiating type I IFN responses that activate antitumor immunity. However, chronic activation of this pathway can paradoxically promote tumor progression and immune suppression, depending on the tumor context [168]. HMMR overexpression activates AURKA kinase, disrupting the cortical localization of ARPC2, which leads to chromosomal missegregation and micronucleus formation. This activation triggers the cGAS/STING pathway, promoting EMT and pro-tumor inflammatory responses via non-canonical NF-κB signaling, thereby enhancing tumorigenesis and remodeling the TME in BRCA1-mutant breast cells [111]. HMMR also facilitates tumor cell sensitivity to DNA damage by promoting the activation of the cGAS/STING/IFN signaling pathway. Specifically, HMMR expression enables STING-mediated apoptotic signaling. During breast cancer lung metastasis, the loss of HMMR weakens this pathway, allowing tumor cells to survive and proliferate in the high ROS and TGF-β-enriched lung microenvironment [135]. These findings suggest that HMMR may promote immune evasion by inhibiting the cGAS/STING signaling pathway, and targeting HMMR could enhance the efficacy of immunotherapy.

HMMR and other signaling pathways
The Rho/ROCK signaling pathway plays a pivotal role in regulating cytoskeletal dynamics, cell migration, and invasion [169]. HMMR enhances tumor cell motility by activating the RHO/ROCK signaling pathway. Studies have shown that in RB-deficient prostate cancer, HMMR activates this pathway, regulating cofilin phosphorylation (p-cofilin) and stabilizing F-actin, leading to cytoskeletal remodeling and increased tumor cell motility and invasiveness. Inhibition of HMMR reduces p-cofilin levels, significantly impairing cell migration and invasion [66]. Additionally, high HMMR expression is strongly associated with metastasis and poor prognosis in breast cancer and melanoma. The Rho inhibitor Rhosin significantly suppresses tumor cell adhesion to the ECM by inhibiting the RhoA/C-YAP pathway, thereby downregulating HMMR expression [136]. These findings highlight HMMR as a key regulator in the RHO/ROCK signaling pathway and suggest its potential as a target for inhibiting tumor metastasis.
The β-catenin signaling pathway is a key component of Wnt signal transduction, essential for regulating cell fate determination, stem cell self-renewal, and tumorigenesis [170]. HMMR has been shown to inhibit GSK-3β-mediated β-catenin degradation in an HA-dependent manner, promoting its nuclear translocation. In fibrosarcoma, LMW-HA binds to HMMR, enhancing its interaction with β-catenin and preventing its degradation. This stabilization leads to β-catenin nuclear translocation, activating the Wnt/β-catenin signaling pathway and inducing the expression of downstream targets such as c-Myc and cyclin D, thereby promoting tumor cell proliferation [171, 172]. Furthermore, β-catenin nuclear translocation enhances its active form within the nucleus. Knockdown of HMMR significantly attenuates FOXM1 overexpression-induced bladder cancer growth, invasion, partial EMT, and Wnt/β-catenin pathway activation, thereby suppressing tumor invasion and metastasis [68].

The dual activity of HMMR
HMMR is commonly recognized as an oncogenic factor across various cancers, with its overexpression closely linked to increased cell proliferation, migration, and metastatic potential (Table 2). High HMMR expression is often associated with poor clinical outcomes and can serve as a useful marker for prognostic evaluation and risk stratification in tumor patients [186].
Prior research has indicated that in human seminomas, approximately 90% of cases show downregulated HMMR expression. The loss of HMMR leads to abnormal detachment of undifferentiated spermatogonia from the basal membrane, along with defects in spindle assembly and disrupted mitotic polarity. This results in germ cell depletion, testicular atrophy, and the formation of carcinoma in situ-like lesions, which may precede seminoma development [187]. HMMR deletions have also been observed in nearly half of neurofibromatosis type 1-associated malignant peripheral nerve sheath tumors, where such deletions may accelerate malignant progression by compromising spindle integrity and cell cycle regulation [188]. These studies highlight the context-dependent nature of HMMR, with its functional consequences tightly linked to the cellular and microenvironmental setting. Interestingly, further studies have shown that partial downregulation of HMMR can suppress the proliferation and migration of pancreatic cancer cells, whereas more complete loss paradoxically enhances migratory capacity in certain PDAC cell lines [65, 189]. Moreover, HMMR plays a tumor suppressive role through the induction of tumor cell apoptosis and the limitation of clonal selection. Studies have shown that loss of HMMR does not significantly affect the initiation or growth of primary breast tumors; however, in a lung microenvironment rich in ROS and TGF-β, its absence weakens STING-dependent DNA damage sensing and interferon signaling, lowers tumor cell sensitivity to DNA damage induced apoptosis, and favors the survival of damage tolerant clones, thereby facilitating pulmonary metastasis [135]. In summary, the role of HMMR across different tumor types and microenvironments exhibits strong context dependency, as its downregulation may under certain conditions restrict tumor cell invasion and migration, thereby exerting potential tumor-suppressive effects. These findings suggest that HMMR should not be simply classified as either an oncogene or a tumor suppressor, but rather as a microenvironmental sensor whose function depends on the dynamic balance of intracellular and extracellular signaling networks [189]. This duality not only underscores the complexity of tumor biology but also implies that future therapeutic strategies targeting HMMR should be tailored to the specific tissue context and microenvironmental characteristics in order to achieve truly precise regulation.
Moreover, this duality suggests that the impact of HMMR may differ even within subtype of the same cancer. Most existing studies lack stratified analyses of specific tumor subtypes. Given the marked differences in metabolic dependency, driver gene mutations, and immune context across subtypes, the functional role of HMMR may vary considerably. Thus, elucidating the subtype-specific heterogeneity of HMMR is crucial for understanding its dual effects and clinical applicability. Studies have shown that in the C1 subtype of intrahepatic cholangiocarcinoma, HMMR is highly expressed, accompanied by active glycolysis/hypoxia and upregulation of inflammation-related pathways, and is simultaneously associated with lymph node metastasis, KRAS/TP53 mutations, and poor survival, thereby indicating an unfavorable prognosis. However, in the C2 subtype, HMMR expression is relatively low [190]. Moreover, in breast cancer, genetic variants of HMMR are linked to an increased cancer risk in BRCA1 mutation carriers, whereas no such associations have been observed in BRCA2 mutation carriers [191]. These observations indicate that the tumor context and subtypes critically influence the function of HMMR. This is particularly relevant in cancers such as HNSCC, where prognosis and therapeutic response differ according to whether the tumor is associated with human papillomavirus infection [192]. Furthermore, clinical translation of HMMR remains at a relatively early stage. Recent clinical evidence has demonstrated that HMMR is broadly overexpressed in bladder carcinoma in situ and correlates with an immunosuppressive TME as well as unfavorable therapeutic outcomes. Nevertheless, its translational utility appears limited, largely due to biological complexity, lack of specificity, and only modest predictive capacity when evaluated as a stand-alone marker. Other biomarkers such as CD44v6 and tumor-associated macrophages have shown stronger prognostic and predictive value. Collectively, these findings suggest that, given the present state of research, HMMR is more appropriately positioned as an auxiliary rather than a stand-alone clinical biomarker [193].

Discussion
In the era of personalized medicine, reliable prognostic biomarkers have demonstrated prognostic significance and clinical relevance across multiple tumor types, hold considerable promise for optimizing cancer treatment strategies [194, 195]. HMMR plays a pivotal role in tumorigenesis across various cancer types and modulates tumor immune responses, positioning it as a promising target for cancer intervention (Fig. 4). As a central integrator linking ECM signals to intracellular mitotic regulation, HMMR is widely overexpressed in multiple malignancies, where it promotes cell proliferation, migration, and metastatic dissemination. Furthermore, HMMR contributes to resistance to immunotherapy by enhancing immune evasion, maintaining CSC phenotypes, and fostering the development of an immunosuppressive TME. Notably, elevated HMMR expression is closely linked to poor clinical outcomes, highlighting its clinical value as a prognostic biomarker.
This review explores the pivotal role of HMMR in cancer development and its involvement in various tumor-associated signaling pathways. HMMR is essential in regulating key biological processes such as cell proliferation and migration [49]. Notably, HMMR lacks the classical hydrophobic transmembrane domain typically required for membrane integration and its membrane localization is likely mediated by glycosylphosphatidylinositol anchoring or interactions with adaptor proteins [196]. Through this noncanonical mechanism, HMMR engages in functional interactions with a variety of transmembrane receptors, including CD44, PDGFR, and RON [115, 174, 197, 198]. These interactions enable HMMR to function as a key extracellular receptor that integrates microenvironmental signals with oncogenic pathways, thereby promoting tumor proliferation, survival, and invasion. Additionally, HMMR can localize to the nucleus and associate with various microstructures, including actin filaments, centrosomes, microtubules, and the mitotic spindle, influencing both cell motility and proliferation [25, 108, 199]. HMMR also interacts with multiple mitosis-associated regulatory proteins to modulate the orderly assembly of microtubules and ensure precise spindle positioning [47, 51], thereby maintaining the fidelity of mitotic division. Collectively, these findings underscore HMMR as a multifunctional protein that coordinates extracellular signaling with intracellular cytoskeletal regulation, contributing to cancer progression through diverse mechanisms.
As a receptor for HA in the ECM, HMMR is involved in promoting EMT, maintaining CSC properties, and facilitating the formation of an immunosuppressive TME. These functions contribute to immune evasion, therapeutic resistance, and reduced efficacy of chemotherapeutic agents [119, 139, 165, 184]. Together, these biological roles position HMMR as a promising therapeutic target with significant potential for clinical application in cancer precision therapy. However, practical pharmacological targeting of HMMR remains challenging due to its predominant coiled-coil α-helical structure, which lacks conventional binding pockets or allosteric sites for small-molecule inhibitors [200]. Nevertheless, peptides targeting the HA-binding domain of HMMR or HA fragments have shown promising progress as alternative therapeutic strategies [201], they exhibit anti-cancer potential mainly by blocking the HA/HMMR signaling pathway, leading to TGF-β downregulation, suppression of fibroblast overactivation, and inhibition of HA induced tumor cell migration, thereby limiting tumor-associated inflammation, angiogenesis, and fibrosis [144, 202]. Notably, in breast cancer cells HMMR-selective peptides significantly inhibited cell growth and activated caspase-3, while displaying no appreciable cytotoxic effects on normal cells, indicating tumor-selective activity [203]. These researches elucidate the multifaceted roles of targeting peptides in regulating tumor signaling pathways and remodeling the TME, underscoring the feasibility of developing peptide-based interventions as novel, safe, and effective anti-cancer agents. Despite these encouraging results, significant limitations remain, most studies on HMMR-targeting peptides have been limited to in vitro assays, with few in vivo evaluations As preclinical results may not fully predict human outcomes, additional validation is required to address potential risks of immunogenicity, in vivo toxicity or diminished effect that could compromise the overall safety and translational applicability [204]. Furthermore, owing to their physicochemical limitations, peptides often exhibit poor stability, short half-lives, and rapid degradation in serum, resulting in low bioavailability [205]. Therefore, the need for repeated administrations to maintain therapeutic levels also restricts their systemic clinical application. In addition to peptide-based strategies, harnessing the immunogenicity of HMMR tumor-associated antigens for therapeutic vaccination has been proposed as another approach. Previous studies have demonstrated that vaccination with xenogeneic HMMR can induce CD8+ T cell responses, hinting at enhanced antitumor effects in the graft context [206]. A subsequent early-phase clinical trials have also demonstrated HMMR-derived peptide vaccines can safely induce CD8+ T cell responses with partial control of tumor burden, accompanied by shifts in peripheral immune subsets. These findings suggest that their antitumor efficacy is governed by the balance between effector activation and immunosuppressive regulation, highlighting their potential in immunotherapy [207, 208]. However, this approach is limited by poor tumor specificity, as HMMR is similarly expressed in leukemia and normal hematopoietic stem cells, as well as broadly upregulated in proliferating cells, raising concerns about selectivity and safety [209]. Dendritic cell based peptide delivery has emerged as an effective strategy in cancer immunotherapy recently, enabling the efficient transfer of tumor-associated antigens to host effector cells, thereby inducing broad anti-tumor T cell responses. Owing to the restricted expression of HMMR in normal tissues, this targeted approach is expected to reduce nonspecific toxicity. Nevertheless, current evidence is confined to preclinical and early clinical studies, and confirmation in large-scale clinical trials is still lacking [210, 211]. Beyond these strategies, several clinically approved drugs have shown potential for targeting HMMR. For example, 4-methylumbelliferone, initially approved for the treatment of biliary spasms, inhibits HA synthesis and exhibits significant anti-tumor activity in cancer models [212]. This drug repurposing approach provides a novel avenue for therapeutic intervention targeting the HA/HMMR axis and may expand the possibilities for HMMR-targeted cancer therapy.
Recent advancements in artificial intelligence (AI)-driven technologies have significantly improved the accuracy of structural predictions for key HMMR domains, enhancing our understanding of the HA/HMMR binding mechanism. This progress enables the rational design and screening of non-canonical yet functionally effective mimetic peptides [213]. By leveraging deep learning, researchers can automatically extract sequence–structure features and integrate multi-omics data, thereby improving the accuracy of anticancer peptide prediction and neoantigen identification. This not only accelerates the discovery and optimization of HMMR-targeting peptides but also promotes the development of personalized immunotherapy strategies [214]. Moreover, with advances in antibody engineering and drug delivery technologies, emerging delivery platforms have enabled the effective incorporation of anticancer agents and demonstrated encouraging efficacy in early-phase clinical trials, highlighting their potential to achieve tumor-selective cytotoxicity [215]. The integration of nanozymes with peptides has attracted increasing attention, as such composite systems not only preserve the precise targeting ability and low immunogenicity of peptides but also impart enzyme-like catalytic activity, thereby enhancing therapeutic responses within the tumor microenvironment [216]. Recent studies have shown that HA-functionalized nanocarriers can exploit the aberrant overexpression of the HMMR receptor in tumor cells to achieve active uptake and tumor-specific drug accumulation. This mechanism has been demonstrated to improve delivery selectivity and reduce systemic toxicity in colorectal cancer, while in triple-negative breast cancer models it further enhances drug accumulation and synergistic cytotoxicity through HMMR-mediated targeting [217, 218]. In the future, the integration of AI-assisted screening of high-affinity functional peptides with nanozyme-based targeted delivery and theranostic capabilities may address challenges in target recognition and drug delivery. Such a strategy could provide a more efficient, specific, and responsive approach to HMMR-targeted interventions, opening the door to novel precision therapies for HMMR-associated diseases. Moreover, given that HMMR may function as a tumor suppressor in certain cancer types, future research and targeted therapeutic strategies must account for its tumor-specific and context-dependent characteristics. Thus, future therapeutic strategies should not only optimize delivery and specificity but also integrate biomarker-guided patient stratification to ensure precision and feasibility in clinical practice.

Conclusions
HMMR serves as a multifunctional hub, linking ECM signals to diverse intracellular pathways that drive cancer initiation, progression, and metastasis. Its aberrant overexpression in various malignancies underscores its clinical value as both a prognostic biomarker and a potential therapeutic target. Functionally, HMMR coordinates essential processes such as mitotic spindle organization, cell polarity, and cytoskeletal remodeling, while modulating the TME and sustaining CSC properties. However, its structural properties and broad physiological roles pose significant challenges for direct targeting with conventional drugs. Promising strategies, including peptide mimetics, HA synthesis inhibition, and vaccines, are emerging to address these obstacles. In conclusion, further exploration of the functions of HMMR in tumors and diverse contexts is essential to fully understand its structural and functional diversity. Continued research on HMMR will contribute to enhanced prognostic assessment and the development of innovative therapeutic interventions, ultimately improving clinical outcomes and quality of life for cancer patients.