CMTM6 is recognized as a key regulator of PD-L1 protein stability. By binding to PD-L1, it prevents lysosomal degradation, thereby increasing PD-L1 expression on the surface of tumor cells and facilitating tumor immune evasion (Fig. 1). This function, validated across multiple cancer types, represents one of the most well-established and critical biological roles of CMTM6 (4,16–18). Through positive regulation of PD-L1, CMTM6 markedly contributes to tumor progression and PD-L1 expression itself holds considerable clinical relevance in several malignancies (19–21). In vitro and in vivo studies have both reported that loss of CMTM6 markedly reduces PD-L1 levels, thereby alleviating suppression of tumor-specific T-cell activity (4,16). CMTM6 exhibits high specificity for PD-L1; its depletion decreases PD-L1 expression without affecting the surface levels or transcription of major histocompatibility class I molecules (22,23). Moreover, CMTM6 expression levels are notably positively associated with CD58. Under CMTM6-deficient conditions, the expression of T-cell activation-related markers, such as CD137 and IL-2, is markedly downregulated. Mechanistically, CMTM6 serves as a critical regulator of CD58 protein stability, physically interacting with CD58 on recycling endosomes and protecting it from lysosomal degradation, thereby maintaining its cell surface expression (24,25). However, PD-L1 and CD58 compete for binding to the MARVEL domain of CMTM6. When PD-L1 expression is upregulated, its competitive advantage displaces CD58 from CMTM6 binding, leaving CD58 unprotected and shunting it toward the lysosomal degradation pathway (10,24,25). Additionally, a study reported that Hsc70 competes with CMTM6 for binding to PD-L1, with both proteins sharing the same PD-L1 binding region (amino acids 161–241). Knockdown of CMTM6 enhances the interaction between Hsc70 and PD-L1, promoting PD-L1 degradation via the endosomal microautophagy pathway (26).

Within the Wnt/β-catenin signaling pathway, CMTM6 interacts with membrane-bound enolase-1 (ENO-1), activating the AKT/glycogen synthase kinase-3β (GSK3β) axis and thereby modulating Wnt signaling. This mechanism is closely associated with the maintenance of cancer stem cells, epithelial-mesenchymal transition (EMT) and resistance to cisplatin (27). Furthermore, CMTM6 regulates the Wnt pathway via β-catenin and is positively associated with infiltration of CD66b+ neutrophils (28). In the ERK1/2 signaling pathway, exosomal CMTM6 promotes ERK1/2 phosphorylation in macrophages, enhancing the expression of M2 macrophage markers such as IL-10, arginase-1 and CD163, thereby inducing M2 polarization (29). Concurrently, CMTM6 suppresses activation of the pRB/E2F pathway, leading to inhibition of hepatocellular carcinoma (HCC) cell proliferation, reduced colony formation and G₀/G₁ phase cell cycle arrest (30). Additionally, CMTM6 activates the MAPK signaling pathway while inhibiting MAPK/ERK phosphorylation, which collectively promotes cell proliferation, migration, invasion and EMT, and simultaneously suppresses sodium-iodide symporter expression and apoptosis (31).

The expression of CMTM6 is also closely associated with activation of the mTOR signaling pathway. Knockdown of CMTM6 results in the downregulation of key mTOR pathway proteins, including phosphorylated mTOR and phosphorylated p70S6 kinase (32). Conversely, overexpression of CMTM6 upregulates critical components of the PI3K/AKT/mTOR and MAPK pathways, such as PI3K, AKT, MEK and ERK, thereby stabilizing the HER2 protein and inhibiting its ubiquitination (33). In cervical cancer (CC), CMTM6 promotes EMT and metastasis through the MAPK JNK/p38 pathway, characterized by decreased E-cadherin and increased vimentin expression. Additionally, CMTM6 suppresses the proliferation of endocervical adenocarcinoma (ECA) through the p53 pathway (34,35). Previous studies that performed RNA sequencing on CMTM6-knockdown ECA cell lines reported that differentially expressed genes were notably enriched in the p53 signaling pathway. Subsequent in vitro functional assays demonstrated that small interfering RNA-mediated CMTM6 knockdown markedly promoted the proliferative capacity of ECA cells, and this effect was mediated through activation of the p53 pathway (34,35). Gene set enrichment analysis further revealed a positive association between high CMTM6 expression and activation of the IL-6-JAK-STAT3 signaling pathway, suggesting a role in inflammation-related signaling and indirect promotion of tumorigenesis (36). Moreover, CMTM6 has been reported to regulate C-C motif chemokine ligand (CCL)4 expression through the AKT/GSK3β/β-catenin pathway in a PD-L1-independent manner, indicating a distinct mechanism involved in tumor progression (Fig. 2) (37).

Research has reported that human antigen R (HuR) binds to AU-rich elements within the 3′ untranslated region of CMTM6 mRNA, stabilizing the transcript and upregulating its expression (38). Further research has revealed that the cerebellar degeneration-related protein 1 transcript upregulates CMTM6, potentially by modulating the expression and/or activity of transcription factors essential for CMTM6 expression (39). Experimental evidence also suggests that WEE1 and ATM inhibitors reduce PD-L1 expression by downregulating CMTM6 (40). Concurrently, EMT transcription factors, particularly SNAIL, have been implicated in upregulating CMTM6 expression (41). Yamamoto et al (42) reported that the hepatitis B virus drug entecavir increased PD-L1 expression through upregulation of CMTM6. Additionally, tumor cells may transfer CMTM6 to surrounding cells via exosomes, thereby enhancing PD-L1 expression on tumor stromal cells, including immune cells (29). Furthermore, five microRNAs (miRs), including hsa-miR-545-5p and hsa-miR-514a-3p, have been reported to exhibit a notable negative association with CMTM6 expression (34). Transcription factors such as BCL3, CREB1 and FOXA1 are also predicted to suppress CMTM6 transcription, while E2F4 and ELK1 are potential activators of its expression (34).

In summary, CMTM6 is a widely expressed protein that serves crucial roles in tumor occurrence, development and treatment (24,33,34). It stabilizes PD-L1 and CD58 by protecting them from lysosomal degradation and extending their protein half-lives, thereby modulating the activation threshold of T cells. CMTM6 is also involved in multiple signaling pathways and is regulated at several levels by factors such as HuR, miRs, EMT transcription factors and antiviral therapeutics. Additionally, CMTM6 can be horizontally transferred via exosomes. Together, these mechanisms enable CMTM6 to promote tumor immune evasion and cancer progression, highlighting its potential as a promising target for cancer immunotherapy.

A comprehensive study integrating data from databases such as The Cancer Genome Atlas, Human Protein Atlas and The Cancer Proteome Atlas analyzed the expression patterns and genetic alteration profiles of CMTM6 across 33 cancer types, alongside its relationship with the tumor immune microenvironment (TIME) (Fig. 3) (43). The findings revealed that CMTM6 expression exhibits notable cancer type specificity and is closely associated with the TIME, particularly PD-L1 expression and immune cell infiltration. Moreover, CMTM6 demonstrated independent prognostic value in multiple types of cancer. These results highlight its potential as both a target for immunotherapy and a prognostic biomarker (Table I) (43).

Lung cancer is one of the most prevalent and deadly malignancies worldwide, encompassing two primary categories: Small cell lung cancer (SCLC) and non-SCLC (NSCLC) (44,45). The development and progression of lung cancer involve complex signaling pathways that regulate key cellular processes, such as proliferation, survival, metastasis and therapeutic resistance (46). In NSCLC, CMTM6 expression is markedly elevated compared with that in normal tissues (47). Immunodetection studies have reported the presence of CMTM6 not only in cancer cells but also in tumor-associated macrophages, lymphocytes and adjacent bronchial epithelial cells (48,49). A retrospective analysis of patients with NSCLC revealed that CMTM6 expression exhibits histological subtype specificity in lung cancer, with notably higher levels in squamous cell carcinoma than in adenocarcinoma. Additionally, patients exhibiting high CMTM6 expression demonstrated a shorter overall survival (OS) time than those with low expression levels. Furthermore, CMTM6 expression was found to be elevated in cases with tumor-infiltrating lymphocytes (TILs) when compared to cases without such infiltration (47,50). In lung adenocarcinoma, CMTM6 is markedly upregulated and notably associated with advanced T stage and lymph node metastasis (36). In patients with lung squamous cell carcinoma (LUSC), CMTM6 expression has been reported to be positively associated with PD-L1 at both mRNA and protein levels. Furthermore, CMTM6 expression is positively associated with infiltration of CD8+ T cells, macrophages, neutrophils and dendritic cells, while it is negatively associated with CD4+ T-cell infiltration, underscoring its notable role in modulating immune cell dynamics within the LUSC tumor microenvironment (TME) (51). Additionally, in SCLC, elevated CMTM6 expression has been reported in high-risk patient subgroups, suggesting its association with specific immune phenotypes and supporting its role as a novel independent prognostic factor (52).

HCC, the most common form of primary liver cancer, poses a notable global health challenge due to its prolonged latency period and lack of distinct early symptoms, often resulting in late-stage diagnosis and high mortality rates (53–55). Numerous studies have reported that elevated CMTM6 expression in HCC is closely associated with tumor progression and poor prognosis. Increased CMTM6 levels are negatively associated with patient survival and positively associated with α-fetoprotein levels (15,56). Mechanistically, CMTM6 promotes tumor cell proliferation by activating the Wnt/β-catenin signaling pathway through stabilization of β-catenin (15). Moreover, CMTM6 facilitates the infiltration of tumor-associated neutrophils and synergizes with PD-L1 to regulate T cell-mediated immune responses (28). It also modulates the infiltration patterns of both CD4⁺ and CD8⁺ T cells within the TME (57). Clinically, high co-expression of CMTM6 and PD-L1 is associated with poor tumor differentiation, micro-intrahepatic metastasis, frequent recurrence, and consequently, shorter overall and recurrence-free survival in patients with HCC (58).

Moreover, CMTM6 promotes the proliferation and invasion of HCC cells by stabilizing vimentin, thereby inducing EMT (56). Elevated CMTM6 expression has been associated with increased Ki-67 levels and shorter recurrence-free survival (59). Additionally, CMTM6 promotes HCC recurrence by regulating the expression of B7 family ligands, suggesting its potential as both a biomarker for HCC recurrence risk and a therapeutic target (59). Furthermore, in the macrotrabecular-massive (MTM) subtype of HCC, co-expression of CMTM6 and PD-L1 is associated with higher inflammatory cell density and elevated PD-L1 expression, which corresponds with increased risks of HCC progression and mortality. An immune classification system based on CMTM6/PD-L1 co-expression effectively stratifies patients with MTM HCC by prognosis, highlighting the potential of CMTM6 as a biomarker and therapeutic target in HCC management (60). By contrast, Huang et al (30) and Zhu et al (61) reported low CMTM6 expression in HCC tissues, with higher CMTM6 levels associated with improved patient prognosis (30,61,62). Huang et al (30) reported that downregulation of CMTM6 in HCC cells reduced p21 levels, leading to activation of the pRB/E2F1 pathway and promoting G₁/S phase transition (Fig. 4).

Based on the relevant literature, three principal factors account for the discrepancies regarding CMTM6 in HCC. First, the etiological heterogeneity across cohorts, including variations in hepatitis virus type, the presence of cirrhosis, histological subtype and metabolic dysfunction-associated fatty liver disease, markedly influences the TIME. Second, CMTM6 exhibits bidirectional, context-dependent functions; it stabilizes PD-L1 to suppress antitumor immunity, binds to p21 to inhibit G₁/S transition, or interacts with vimentin to promote EMT, with the net effects varying according to the molecular partner involved. Third, the complexity of TIME further diversifies the observed outcomes. Wei et al (32). reported that the co-expression of CMTM6 and PD-L1, along with CD4⁺ T-cell infiltration, was associated with a favorable prognosis, whereas Kong et al (28) revealed that CMTM6 can promote tumor-associated neutrophil infiltration through the Wnt/β-catenin pathway, which is associated with a poor prognosis. Furthermore, differences among studies regarding sample size, clinical stage distribution, detection methodologies and assessment criteria may contribute to the inconsistent conclusions.

CRC ranks as the third most commonly diagnosed cancer and the second leading cause of cancer-related mortality worldwide (63,64). Its complexity is driven by diverse signal transduction networks that regulate cellular proliferation, survival, differentiation and apoptosis (65). CMTM6 expression has been reported to be elevated in CRC tissues compared with that in matched normal tissues, with high CMTM6 levels associated with increased PD-L1 expression and greater immune cell infiltration (66). Notably, CMTM6 levels tend to be lower in advanced-stage CRC tumors compared with those in early-stage tumors. High CMTM6 expression is associated with lower pathological T stage and increased density of TILs, suggesting a notable role for CMTM6 in modulating the TIME (67). Moreover, Wu et al (68) reported that in patients with rectal cancer undergoing PD-1/PD-L1 inhibitor therapy, CMTM6 expression in M2 macrophages can serve as a promising biomarker for predicting treatment response. Furthermore, an immunohistochemical analysis of a tissue microarray from 704 patients with CRC assessing β-catenin, CMTM6, PD-L1 and mismatch repair protein expression revealed a positive association between CMTM6/PD-L1 co-expression and β-catenin levels, suggesting that CMTM6/PD-L1 may influence the immune microenvironment via the Wnt/β-catenin signaling pathway (69).

Liver metastasis of CRC is a major contributor to CRC-related mortality (70). A study reported that CMTM6 promotes CRC liver metastasis by mediating the Warburg effect. Mechanistically, CMTM6 forms a complex with glucose transporter 1 (Glut1) and Rab11 in the endoplasmic reticulum, facilitating Rab11-dependent trafficking of Glut1 to the plasma membrane, which enhances glucose uptake and glycolysis (71). CMTM6 serves a critical role in sustaining CRC cell cycle progression and liver metastasis, contrasting with its function in HCC, where it suppresses G₁ to S phase transition by stabilizing p21 and inactivating the pRB/E2F pathway (30).

GC is a complex and heterogeneous disease characterized by marked phenotypic and genetic variability (72). Studies have reported that CMTM6 expression is markedly elevated in GC tissues compared with that in normal gastric tissues, with even higher levels observed in advanced-stage disease (73). Immunohistochemical analysis of 122 postoperative GC tissue specimens revealed a notable association between CMTM6 and PD-L1 protein expression (74). A retrospective study involving 105 patients with stage II/III GC performed by Nishi et al (75) reported markedly lower 5-year OS and disease-free survival rates in the CMTM6 high-expression group compared with that in the low-expression group, supporting the role of CMTM6-mediated immune escape via PD-L1 (75). Furthermore, immunohistochemical staining of 185 GC specimens from radical gastrectomies indicated that high co-expression of CMTM6 and PD-L1 was notably associated with Borrmann type, lymph node metastasis, peritoneal metastasis and Tumor-Node-Metastasis stage, but showed no association with patient age, sex, tumor size, differentiation grade, tumor location or T stage. Survival analysis further demonstrated that high CMTM6 expression was associated with a shorter OS and worse prognosis, with the worst outcomes observed in cases with concomitant high PD-L1 expression (76). Additionally, in gastric adenocarcinoma, CMTM6 expression has been shown to be higher in tumor tissues than in adjacent normal tissues, and to be positively associated with PD-L1 expression in both epithelial and stromal compartments. CMTM6 expression also showed positive associations with tumor burden and the Ki-67 proliferation index, indicating that membrane co-expression of CMTM6 and PD-L1 on tumor epithelial cells serves as a marker of poor prognosis in gastric adenocarcinoma (77).

PC remains one of the most lethal malignancies worldwide, with limited advances in effective treatments over recent decades (78,79). Notably, studies have identified upregulated CMTM6 expression in pancreatic adenocarcinoma tissues (40,80). Functional analyses have demonstrated that CMTM6 promotes the proliferation, migration and invasion of PC cells (80). CMTM6 expression has also been reported to be positively associated with PD-L1 levels, and CMTM6 has been shown to co-immunoprecipitate with PD-L1 protein in PC cell lines. Upregulation of CMTM6 contributes to shaping an inflammatory TME characterized by a heightened immune response (80). Furthermore, research has indicated that inhibition of WEE1, alone or in combination with ATM inhibition, downregulates PD-L1 expression by blocking phosphorylation of GSK3β at serine 9 and reducing CMTM6 levels. In Capan-1 mouse xenograft models, treatment with AZD1775 (a WEE1 inhibitor) combined with AZD0156 (an ATM inhibitor) has been shown to reduce tumor growth and downregulate the expression of PD-L1, CMTM6, CD163 and CXCR2 in tumors, factors known to contribute to tumor immune evasion (40).

CC, primarily driven by human papillomavirus infection, is considered preventable and manageable due to its well-established etiology (81,82). CMTM6 serves a critical role in CC, with its expression closely associated with the biological behavior of the tumor. Studies have reported that CMTM6 expression is markedly upregulated in CC tissues compared with that in adjacent non-cancerous tissues, and positively associated with PD-L1 expression. This co-expression is strongly associated with poor patient prognosis (13,83). In vitro experiments have demonstrated that CMTM6 promotes invasion, migration, proliferation and EMT of CC cells by activating the MAPK JNK/p38 signaling pathway (34). Conversely, CMTM6 inhibits the proliferation of ECA cells through the p53 pathway and recruits T cells, thereby enhancing the antitumor immune response (35). The multiple molecular functions of CMTM6 underpin its dual role; it stabilizes PD-L1 to suppress antitumor immunity, binds to p21 to inhibit G₁/S transition, or interacts with vimentin to promote EMT, with the net effects varying according to the molecular partner involved.

Within the TIME, CMTM6 expression has been reported to be positively associated with immune checkpoint components. Silencing CMTM6 increases infiltration of CD8⁺ and CD4⁺ T cells while reducing the proportion of exhausted T cells (84). Moreover, soluble CMTM6 levels are markedly elevated in the plasma of patients with CC and are positively associated with exosomal PD-L1, suggesting a role for CMTM6 in tumor immune evasion via the exosomal pathway (85). A recent study further reported that exosomes secreted by CC cells carry CMTM6, which activates the mTOR signaling pathway in macrophages, inducing M2a polarization. These M2a macrophages subsequently secrete CCL2, enhancing the migration and invasion of CC cells, and promoting disease progression (13). Collectively, these findings highlight CMTM6 not only as a potential prognostic biomarker for CC but also as a promising target for immunotherapy.

Breast cancer is the most common malignancy among women worldwide. Triple-negative breast cancer (TNBC), which accounts for 10–20% of all breast cancer cases, is an aggressive subtype associated with a poor prognosis (86). A study reported that CMTM6 expression is markedly higher in patients with TNBC compared with that in those with HER2-positive breast cancer (87). Moreover, elevated CMTM6 levels are associated with shorter progression-free survival (PFS) in patients with TNBC, and multivariate Cox regression analysis has identified CMTM6 as an independent risk factor for PFS (87). Furthermore, CMTM6 expression has been reported to be positively associated with both the EMT score in breast cancer cell lines and the key EMT marker vimentin in TNBC (41). In SNAI1-induced MCF-7 cells (MCF-7-Mes), acquisition of a mesenchymal phenotype leads to increased PD-L1 and CMTM6 expression. Silencing CMTM6 in MCF-7-Mes cells partially reduces PD-L1 surface expression, indicating that PD-L1 expression is partially dependent on CMTM6. Furthermore, dual knockdown of CMTM6 and CMTM7 markedly decreases PD-L1 surface expression, suggesting that these proteins cooperatively regulate PD-L1 levels (41,88). Additionally, research has reported that hsa_circ_0067842 upregulates CMTM6 expression via HuR, while knockdown of HuR reduces CMTM6 mRNA stability. These findings establish the hsa_circ_0067842/HuR/CMTM6/PD-L1 axis as a potential prognostic biomarker and therapeutic target for breast cancer immunotherapy (89).

OSCC, the predominant subtype of head and neck squamous cell carcinoma, has a 5-year survival rate of <50%, with its precise etiology still unclear (90–92). CMTM6 holds notable clinicopathological relevance in OSCC, as its high expression is closely associated with tumor progression and poor prognosis. A study reported that both CMTM6 and neuropilin-1 (NRP1) are upregulated in OSCC tissues and physically interact. NRP1 contributes to the degradation of CMTM6, while CMTM6 promotes tumorigenesis by inducing NRP1 expression (93). Furthermore, CMTM6 expression is positively associated with PD-1 and PD-L1 levels, suggesting a potential synergistic role in immune pathways that facilitate tumor immune escape in OSCC (94). CMTM6 can also be transferred to macrophages via exosomes, where it activates the ERK1/2 signaling pathway and induces M2 macrophage polarization, thereby promoting malignant progression of OSCC (95). Additionally, research has shown that CMTM6 interacts with membrane-bound ENO-1 to activate the AKT/GSK3β axis, which modulates the Wnt signaling pathway, driving EMT and cisplatin resistance (27). Thus, CMTM6 not only regulates tumor cell behavior in OSCC but also markedly influences the immune microenvironment, underscoring its potential as a therapeutic target (Fig. 5).

Melanoma, which arises from melanocytes, is the most lethal form of skin cancer (96,97). In melanoma, CMTM6 expression has been reported to be markedly associated with several immune markers, including PD-L1, CD3, CD20 and CD68. Furthermore, high CMTM6 expression within stromal and immune compartments has been shown to be significantly associated with improved survival following immunotherapy (P=0.007) and demonstrates notable prognostic value in multivariate analyses (98). Furthermore, high co-expression of CMTM6 and PD-L1 in the stromal compartment has been significantly associated with prolonged survival (P=0.028), highlighting CMTM6 as a potential predictive biomarker for immune checkpoint inhibitor therapy (98). Further studies have reported that CMTM6 is essential for maintaining CD58 stability in melanoma, where intact CD58 expression and its interaction with CD2 are critical for effective antitumor immunity. When CD58 is lost, CMTM6 facilitates PD-L1 upregulation, thereby promoting immune evasion. The competitive interactions among CMTM6, CD58 and PD-L1 regulate their endosomal recycling and lysosomal degradation rates, establishing a molecular mechanism by which cancer cells balance immunosuppressive and immunostimulatory signals (10). Collectively, these findings underscore the marked role of CMTM6 in melanoma immunotherapy, positioning it as both a promising prognostic biomarker and therapeutic target.

Glioma is the most prevalent and aggressive malignant brain tumor in adults, posing notable challenges in oncology due to its rapid progression, therapeutic resistance and poor prognosis (99,100). In glioma, CMTM6 expression is closely associated with several biological processes and therapeutic responses. A study reported that both CMTM6 and CMTM4 are markedly associated with PD-L1 expression in glioma, with macrophages identified as the primary cell type expressing these proteins. High expression levels of CMTM6 and CMTM4 are associated with reduced OS, suggesting their potential as biomarkers for immune-targeted interventions in glioma (101). Moreover, elevated CMTM6 expression in glioma has been associated with poor prognosis. Knockdown of CMTM6 inhibits the proliferation, invasion and migration of U87 and U251 glioma cells, increases apoptosis rates, inactivates the mTOR signaling pathway, and reduces tumor volume and Ki-67 expression (32). CMTM6 is highly expressed in glioma and is strongly associated with the TIME and inflammatory responses (102). A recent study further demonstrated that CMTM6 is markedly upregulated in high-grade glioma and associated with poor patient outcomes. CMTM6 knockout resulted in downregulation of PD-L1 and TGFβ1/2/3, alongside upregulation of pro-inflammatory factors IL-6 and CCL3, promoting microglial polarization toward the M1 phenotype and thereby modulating the immune microenvironment (103). Collectively, these findings underscore the crucial role of CMTM6 in glioma pathogenesis, progression and immune regulation, highlighting its potential as both a diagnostic biomarker and therapeutic target.

Beyond the aforementioned malignancies, CMTM6 serves pivotal roles in several other tumors, with its functional impact and mechanisms differing across cancer types. In ovarian cancer, the most lethal gynecological malignancy, CMTM6 upregulation is paradoxically associated with a more favorable prognosis. This may be attributed to its modulation of immune cell infiltration and the expression of immune cell markers, with copy number variations and DNA methylation implicated in its aberrant expression (104–106). In clear cell renal cell carcinoma, CMTM6 depletion has been reported to notably inhibit cell proliferation, migration and invasion, while enhancing antitumor immunity, evidenced by increased infiltration of CD4+ and CD8+ T cells. Loss of CMTM6 also induces a DNA damage response, leading to cellular senescence and secretion of inflammatory factors (107). In undifferentiated pleomorphic sarcoma, CMTM6 expression has been reported to be strongly associated with high PD-L1 levels, and elevated expression is markedly associated with poor prognosis (108). In thyroid carcinoma, CMTM6 promotes the development of thyroid cancer by inhibiting sodium/iodide symporter activity through activating the MAPK signaling pathway, with its expression closely associated with tumor metastasis (31). In acute myeloid leukemia, FLT3-ITD mutations enhance CMTM6 protein stability through protein-protein interactions, thereby promoting PD-L1 expression and facilitating immune evasion (14). Collectively, these studies underscore the complex and diverse mechanisms through which CMTM6 influences tumor biology, emphasizing its potential as a therapeutic target across multiple cancer types.

Beyond its roles in oncology, CMTM6 has emerged as a key regulator in numerous non-neoplastic pathological conditions. In dry eye disease (DED), reduced CMTM6 expression is associated with increased disease severity. Its downregulation contributes to decreased tear secretion, corneal epithelial defects and heightened inflammatory responses, implicating the CMTM6-NF-κB p65 signaling axis as a potential therapeutic target for DED (109). In primary Sjögren's syndrome, CMTM6 levels are notably elevated in both the serum and labial salivary gland tissues of patients, and are positively associated with PD-1/PD-L1 levels, disease activity (as assessed by EULAR Sjögren's Syndrome Disease Activity Index) and immunological indices, including IgG and erythrocyte sedimentation rate. By contrast, serum CMTM6 levels are negatively correlated with lymphocyte counts and CD3+ T cells (r=−0.397). These findings suggest that CMTM6 may participate in the PD-1/PD-L1 pathway by regulating PD-L1 stability, thereby influencing lymphocyte activation and peripheral immune tolerance (110). Additionally, in Helicobacter pylori-infected gastric mucosal cells, CMTM6 stabilizes PD-L1 protein by preventing its degradation. CRISPR/Cas9-mediated knockout of CMTM6 alters protein ubiquitination and affects the expression of cell surface receptors, highlighting its regulatory role in infection-associated immune modulation (111).

Furthermore, CMTM6 contributes to the pathogenesis of autoimmune diseases. In antineutrophil cytoplasmic antibody-associated vasculitis (AAV), reduced CMTM6 expression leads to increased lysosomal degradation of PD-L1, thereby impairing negative regulatory signaling in T cells. This suggests that targeting lysosomal function could offer a novel therapeutic approach for AAV (112). CMTM6 expression is also upregulated in neutrophils from patients with antiphospholipid syndrome (APS), and neutrophil extracellular traps (NETs) serve a critical pathogenic role in thrombosis associated with APS. It is therefore hypothesized that CMTM6 may contribute to the pro-thrombotic process in APS by promoting or sustaining excessive neutrophil activation and enhancing NET release; however, the underlying molecular mechanisms, including the potential involvement of PD-L1 stabilization or other signaling pathways, remain to be elucidated (113,114). A recent study identified CMTM6 as a key regulator in the pathogenesis of rheumatoid arthritis (RA), acting through the CMTM6-TAK1-NF-κB/MAPK axis to modulate fibroblast-like synoviocyte function and macrophage polarization, thereby promoting RA progression. Targeting CMTM6 thus represents a potential therapeutic direction for RA, although the specific binding sites between CMTM6 and TAK1, as well as the particular ubiquitin ligases and deubiquitinases involved in regulating this axis, require further analysis (115). In summary, CMTM6 has emerged as a promising diagnostic and therapeutic target for several non-neoplastic diseases; however, the precise mechanisms by which CMTM6 influences the onset and progression of autoimmune disorders require further investigation.