Multiple regions on chromosome 3p are commonly affected by loss of heterozygosity in several types of cancer (66). TMEM7 is a candidate tumor suppressor gene located at the 3p21.3 region of the human genome. It is a 232-amino acid, single-pass membrane protein, primarily expressed in the liver (67) and is integral to liver carcinogenesis (Fig. 3). It shares considerable sequence homology with the 28 kDa interferon-α (IFN-α)-responsive protein, suggesting a potential role in immune response modulation (67). TMEM7 has been implicated as a candidate tumor suppressor gene due to its frequent downregulation or inactivation in several types of cancer. Zhou et al (67) examined primary hepatocellular carcinoma (HCC) tissues and HCC cell lines, and found that TMEM7 mRNA expression was downregulated or silenced in 85% of primary HCC samples and 33% of HCC cell lines. This recurrent loss of function suggests that TMEM7 carries out a key role in suppressing hepatocarcinogenesis (67). Mechanistically, the downregulation of TMEM7 is primarily driven by epigenetic modifications such as DNA methylation and histone deacetylation, rather than by genomic deletions or mutations (67-69). To the best of our knowledge, no homozygous deletions or mutations of TMEM7 have been identified in HCC tissues or cell lines.

Zhou et al (67) demonstrated that treatment with DNA methylation inhibitors (such as 5-aza-2'-deoxycytidine) and histone deacetylase inhibitors (such as trichostatin A) can restore TMEM7 expression in knockdown cell lines, confirming the role of epigenetic alterations in its silencing. Through the ectopic expression of TMEM7 in two HCC cell lines with TMEM7 knockdown, cell proliferation, colony formation and cell migration were inhibited, and tumor formation in nude mice was reduced. After 7 days of IFN-α treatment in two highly invasive HCC cell lines, TMEM7 expression was markedly increased and cell migration was inhibited, further establishing the role of TMEM7 in liver cancer metastasis (67). These findings also suggest that modulating TMEM7 expression via IFN-α may have therapeutic potential for certain patients with HCC. While the role of TMEM7 in HCC is well-documented, its interaction with other genes on chromosome 3p further expands its roles. In a study by Kholodnyuk et al (68) involving human chromosome 3-mouse fibrosarcoma hybrids, the transcription of TMEM7 and its neighboring genes (such as LTF and SLC38A3) was found to be impaired in renal cell carcinoma (RCC) cell lines, suggesting a broader tumor-suppressive role across multiple cancer types (68).

The epigenetic silencing of TMEM7 during hepatocarcinogenesis highlights the functional loss of TMEM7 as a key factor in liver cancer development, while its restoration or upregulation (by IFN-α, for example) offers potential therapeutic benefits (67-69). Understanding the precise role of TMEM7 in liver cancer progression may pave the way for targeted therapies aimed at improving outcomes for patients with this aggressive malignancy.

TMEM25, a member of the immunoglobulin superfamily, carries out a role in various cellular processes, including immune responses, growth factor signaling and cell adhesion (70,71). Its expression is markedly altered in several types of cancer, particularly in triple-negative breast cancer (TNBC), colorectal cancer (CRC) and clear cell RCC (ccRCC), making it a promising biomarker for diagnosis, prognosis and therapeutic targeting. The functional importance of TMEM25 in cancer is underscored by a study demonstrating its epigenetic regulation, particularly through DNA methylation and histone modifications, which affect its expression and role in tumorigenesis (71).

In colon adenocarcinoma, Hrašovec et al (70) observed a marked downregulation of TMEM25 mRNA in 68% of tumor tissues from patients with primary colon cancer. This downregulation was linked to hypermethylation of a specific CpG site within the 5' untranslated region of the TMEM25 gene, suggesting that epigenetic silencing through DNA methylation is a key mechanism responsible for the decreased expression of TMEM25 in colon adenocarcinoma. The inverse relationship between TMEM25 hypermethylation and its expression levels underscores the key role of epigenetic regulation in modulating TMEM25 expression during colon carcinogenesis (70). In breast cancer, the expression of TMEM25 is reduced in 50% of tumor samples compared with normal tissues, as reported by Doolan et al (72). Increased TMEM25 expression levels were associated with improved clinical outcomes, particularly in patients undergoing adjuvant chemotherapy, where it was associated with prolonged survival (72). By contrast, TMEM25 expression was often undetectable in TNBC, a subtype of breast cancer that is difficult to treat and associated with poor prognosis (70-72). In TNBC, TMEM25 acts as a suppressor of tumor progression by inhibiting the activation of the STAT3 signaling pathway. Specifically, TMEM25 physically interacts with the EGFR monomer, preventing EGFR-mediated STAT3 phosphorylation. This interaction sequesters unphosphorylated STAT3 in the cytoplasm, thereby inhibiting its nuclear translocation and subsequent tumor-promoting gene transcription (12,71,72). However, in TMEM25-deficient TNBC cells, EGFR monomers can phosphorylate STAT3 independently of ligand binding, leading to basal STAT3 activation and tumor progression. Restoring TMEM25 expression through adeno-associated virus delivery has been revealed to suppress STAT3 activation and TNBC progression in preclinical models, highlighting its potential as a therapeutic target (12,71,72). These findings indicate that TMEM25 may act as a valuable prognostic marker in breast cancer, particularly in predicting patient response to chemotherapy and providing insights into the molecular mechanisms underlying chemotherapy resistance. Growing evidence also indicates that TMEM25 carries out a tumor-suppressive role in ccRCC, a subtype of kidney cancer with limited therapeutic options (73). In ccRCC tissues, elevated DNA methylation of TMEM25 has been observed, suggesting epigenetic silencing in this type of cancer. Moreover, mutations in TMEM25 have been revealed to notably impact patient prognosis, with reduced TMEM25 expression associating with a more aggressive disease phenotype. Notably, the expression of TMEM25 in ccRCC is strongly associated with several immune-related factors, including immune checkpoint molecules, immune suppressive markers and major histocompatibility complex molecules, implying that TMEM25 may be involved in modulating the immune landscape of ccRCC (73). This interaction between TMEM25 and immune-related factors further underscores its role in immune evasion within the TME.

TMEM25 has been identified as a promising prognostic biomarker in colon cancer, breast cancer and ccRCC (70-72). Its expression is regulated epigenetically, primarily through DNA methylation and histone modifications, which suggests that reversing its epigenetic silencing could offer a promising therapeutic approach. Furthermore, the involvement of TMEM25 in immune modulation, especially through its interactions with immune checkpoint molecules, presents considerable promise for immunotherapeutic interventions. This establishes TMEM25 as a key therapeutic target in several types of cancer where its expression is reduced or absent. Given its pivotal role in cancer progression and immune regulation, TMEM25 may serve as a promising therapeutic target. Future research should focus on elucidating the molecular pathways through which TMEM25 influences tumor progression and immune responses. Restoring or enhancing TMEM25 expression could considerably improve treatment outcomes in colon cancer, breast cancer, and ccRCC, thereby positioning it as a promising target in future cancer therapies (70-72).

TMEM88 is a dual-transmembrane protein that participates in several key biological processes, particularly the regulation of human stem cell differentiation and embryonic development (74,75). Previous studies have indicated that TMEM88 carries out a key role in tumorigenesis, with its expression being altered in several types of cancer (74,75). Notably, TMEM88 binds to Dishevelled (DVL), preventing its interaction with LRP5/6 and inhibiting the canonical Wnt pathway. This leads to decreased β-catenin activity and downregulation of Wnt target genes, including c-Myc and cyclin D1 (75). While TMEM88 is widely expressed in various types of tumors, it is typically downregulated in the majority of tumor cells, suggesting its role as a potential tumor suppressor (76).

The expression of TMEM88 is also markedly decreased in thyroid cancer (TC) tissues and cell lines (75-77). Studies have revealed that TMEM88 inhibits the proliferation, colony formation and invasion of TC cancer cells, primarily through binding to DVL (75-77). In both in vitro and in vivo models, overexpression of TMEM88 has been shown to suppress tumorigenic properties, further supporting the role of TMEM88 as a tumor suppressor in TC. These findings suggest that restoring TMEM88 expression or inhibiting its methylation may offer a promising therapeutic strategy for treating TC. The involvement of TMEM88 in bladder cancer has been further emphasized instudies (78,79). Upregulation of TMEM88 in bladder cancer leads to a marked reduction in cellular proliferation and invasion (78,79). Bioinformatic analysis revealed that TMEM88 expression was considerably reduced in bladder cancer tissues compared with normal tissues (79). Zhao et al (79) provided evidence that loss of TMEM88 expression in bladder cancer cells enhances invasive and proliferative capacities, while re-expression of TMEM88 effectively reverses these phenotypes (79). Additionally, overexpression of TMEM88 in bladder cancer xenograft models inhibited tumor growth (79), indicating that TMEM88 acts as a tumor suppressor gene in bladder cancer as well.

The biological role of TMEM88 depends on its subcellular localization. Membrane-localized TMEM88 inhibits Wnt signaling, while cytosolic TMEM88 promotes tumor progression through alternative pathways. Zhang et al (80) reported that cytosolic localization of TMEM88 in non-small cell lung cancer (NSCLC) is associated with poor differentiation, a high TNM stage, lymph node metastasis and worse overall survival (OS). TMEM88 was shown to promote invasion and metastasis by activating the p38-GSK3 β-Snail signaling pathway. Overexpression of TMEM88 in NSCLC cells inhibited excessive cell proliferation, invasion and migration, leading to the prevention of tumor growth in xenograft models (80). Furthermore, hypermethylation of the TMEM88 promoter has been observed in NSCLC tissues, which is associated with a worse prognosis. Demethylation of TMEM88 resulted in the inhibition of cell proliferation, migration and invasion, suggesting that TMEM88 expression and its epigenetic regulation carry out a key role in NSCLC progression (81). In TNBC, TMEM88 overexpression in the cytosol stimulated invasion and metastasis by interacting with DVL proteins and promoting Snail expression while inhibiting tight junction proteins, such as zonula occludens-1 and occluding (82). Thus, increased TMEM88 expression was associated with improved prognosis in HCC and bladder cancer, while its cytosolic localization was predictive of a worse outcome in NSCLC and TNBC.

TMEM88 carries out a key role in regulating cell proliferation, migration and invasion, and has demonstrated notable potential as both a diagnostic biomarker and therapeutic target across various types of cancer (79-82). Its expression is frequently downregulated in tumors, and promoter hypermethylation of TMEM88 is associated with a worse prognosis in NSCLC (80,81). These findings highlight TMEM88 as a potential marker for disease progression and survival prediction. The epigenetic regulation of TMEM88, particularly through DNA methylation, offers a novel therapeutic avenue. Demethylating agents can restore TMEM88 expression (81), thereby suppressing tumor cell growth and metastasis. As a negative regulator of the Wnt/β-catenin signaling pathway, TMEM88 exhibits tumor-suppressive activity in NSCLC, TC and bladder cancer. Therapeutic strategies aimed at restoring or enhancing TMEM88 expression could thus represent a viable approach for cancer treatment. Ongoing research into the molecular mechanisms of TMEM88 is expected to further clarify its value as both a therapeutic target and a prognostic biomarker in clinical oncology.

TMEM106A is located on chromosome 17 and consists of 262 amino acids. TMEM106A is a conserved type II TP that has been implicated in suppressing tumorigenesis across multiple types of cancer (83,84). TMEM106A is typically expressed in normal gastric tissue and is often downregulated or silenced in gastric cancer (GC), due to methylation of the promoter region, and its methylation is associated with smoking and tumor metastasis (83,84). Frequent methylation of TMEM106A in GC tissues highlights its potential role as a tumor suppressor. Xu et al (84) demonstrated that overexpression of TMEM106A markedly inhibited GC cell proliferation and induced apoptosis, while also delaying tumor growth in xenograft models (84). Mechanistic studies suggested that these effects were closely associated with the activation of caspase-2, caspase-9 and caspase-3, as well as the inactivation of poly(ADP-ribose) polymerase (PARP) (84). Thus, TMEM106A has emerged as a functional tumor suppressor in the pathogenesis of GC.

Methylation of TMEM106A is generally associated with its reduced expression and the promoter region methylation serves as a key regulatory mechanism in GC. The downregulation of TMEM106A expression in patients with GC is associated with a worse prognosis, emphasizing its clinical relevance as a prognostic biomarker (85). In renal cancer, TMEM106A expression is markedly reduced, and its restoration in cancer cells leads to attenuated proliferation, reduced migration and enhanced caspase-3-dependent apoptosis (86). Similarly, the expression of TMEM106A in HCC tissues is notably reduced compared with normal liver tissue, accompanied by frequent promoter methylation in HCC tissues, further reinforcing its potential as a tumor suppressor (87). Treatment with 5-Aza-2'-deoxycytidine in HCC cells with high methylation restored TMEM106A expression and markedly suppressed the malignant behaviors of these cells, including reduced cell migration, invasion and lung metastasis (87). In vivo experiments demonstrated that overexpression of TMEM106A in HCC cells resulted in considerable tumor suppression, and this was associated with the suppression of epithelial-mesenchymal transition (EMT) and the inactivation of the ERK1/2/Slug signaling pathway (87). Moreover, in NSCLC, TMEM106A expression was revealed to be markedly decreased in tumor tissues. Overexpression of TMEM106A in NSCLC cells reduced proliferation, migration and invasion, while inducing apoptosis. It also repressed EMT by modulating E-cadherin, N-cadherin and vimentin expression, and inhibited the PI3K/Akt/NF-κB signaling pathway (88). In urothelial carcinoma, TMEM106A was identified as a novel biomarker, with its methylation levels in urine samples revealing high diagnostic accuracy for early detection (89).

TMEM106A also exhibits antiviral activity, specifically in the IFN-mediated antiviral immune response. TMEM106A was revealed to interact with the receptor SCARB2 of EV-A71 and CV-A16, thus disrupting viral binding to host cells and preventing viral infection (90). This finding not only highlights a novel mechanism of TMEM106A in antiviral immunity but also proposes a potential therapeutic target for antiviral strategies. In addition to its antiviral function, TMEM106A regulates macrophage activation and immune responses, especially in bacterial infection-induced inflammation. Its downregulation enhanced M1 macrophage polarization and exacerbated the LPS-induced inflammatory response through the MAPK and NF-κB signaling pathways, underscoring the key role of TMEM106A in immune homeostasis (91).

TMEM106A carries out a key tumor-suppressive role in various types of cancer, such as gastrointestinal tumors, liver cancer and NSCLC, with its dysregulated expression, including methylation, potentially serving as a valuable clinical prognostic biomarker (84,86-91). Furthermore, the diverse functions of TMEM106A in immune responses and antiviral defense establish it as a potential target for future cancer treatments and immune modulation strategies. Further research should prioritize elucidating the specific mechanisms by which TMEM106A operates in various types of cancer and exploring its clinical applications.

TMEM173, also known as stimulator of interferon genes (STING), is a key TP located on the outer membrane of the ER and carries out a key role in cancer immunology and immunotherapy. It is essential in innate immunity and is primarily expressed in hematopoietic cells and immune organs such as the thymus and spleen (92,93). Composed of four transmembrane domains, TMEM173 forms dimers that allow ligand binding and activation of immune responses, in addition to mediating reactions to cytosolic DNA, which can result from infections, cellular stress or genomic instability (94). TMEM173 carries out a key role in host defense against pathogenic infections by regulating type I IFN (IFN-I) signaling, pro-inflammatory cytokines and innate immunity (95). In addition to its role in innate immunity, TMEM173 also contributes to autoimmune inflammation, oxidative stress and autophagy (96).

While TMEM173 has demonstrated tumor-suppressive functions in various cancer types, including CRC, prostate cancer and melanoma (92); it is important to note that TMEM173 activation can act as a double-edged sword in cancer. It promotes antitumor immunity by enhancing dendritic cell (DC) maturation, T cell activation and macrophage polarization toward an M1 phenotype, which supports tumor elimination (97-99). T cell infiltration into tumors is largely dependent on IFN-I signaling, and activation of TMEM173 enhances immune surveillance against tumors. For example, TMEM173 agonists have been revealed to amplify the cGAS-STING pathway, leading to increased IFN-β secretion and T cell-mediated immune responses in colorectal and breast cancer models (97). Additionally, TMEM173 activation can reprogram tumor-associated macrophages (TAMs) from an immunosuppressive M2 phenotype to an immunostimulatory M1 phenotype, further enhancing antitumor immunity (97,100). TMEM173 expression is downregulated in various types of cancer, including GC and HCC, and this downregulation associates with tumor size, invasiveness and lymph node metastasis. In vitro experiments have revealed that knockout of TMEM173 promotes clonal formation, migration and invasion of GC cells, whereas its activation induces apoptosis and autophagy in malignant cells, inhibiting tumor growth (101). However, STING signaling can also promote immune evasion and tumor progression. For example, TMEM173 activation in tumor monocytes induces programmed death (PD)-ligand 1 expression, which suppresses T cell activity and contributes to resistance against TMEM173 agonist therapy (102). Similarly, TMEM173 signaling can expand regulatory B cells that produce IL-35, which attenuates natural killer (NK) cell function and compromises antitumor immunity (103). TMEM173 may carry out a key role in metastasis formation. Activation of TMEM173 promotes metastatic tumor formation and spread, partly through the production of TNF-α and other cytokines (104). For example, Bu et al (105) reported that, in clinical samples from patients with hepatitis B virus (HBV)-induced liver cancer, TMEM173 downregulation may contribute to immune evasion and subsequently facilitate tumor progression.

TMEM173 is not only a key regulator of tumor immunity but also holds substantial therapeutic potential within cancer immunotherapy. Targeting TMEM173, either by modulating its upstream or downstream signaling pathways, may provide novel therapeutic strategies to enhance cancer treatment outcomes, particularly when combined with immune checkpoint blockade therapies (106). Therefore, TMEM173 agonists are emerging as promising candidates for cancer immunotherapy. Nanoparticle-based delivery systems have been developed to enhance the spatiotemporal activation of TMEM173, improving its therapeutic efficacy while minimizing off-target effects (107). For example, TME-responsive nanoparticles have been designed to simultaneously activate TMEM173 and TLR4, leading to enhanced IFN-β production and T cell responses in colorectal and metastatic breast cancer models (97). Additionally, combining TMEM173 agonists with immune checkpoint inhibitors, such as anti-PD-1 antibodies, has shown synergistic effects in preclinical models (97,100). However, challenges remain in translating TMEM173 agonists to clinical practice. Issues such as poor drug stability, limited tumor targeting and immune-related adverse events need to be addressed (103,108). Nanomedicine approaches, including the use of radiosensitizers and targeted delivery systems, are being explored to overcome these limitations.

TMEM173 is a central player in cancer immunology, with its activation driving both antitumor immunity and immune evasion. While TMEM173 agonists hold potential for cancer immunotherapy, their clinical translation requires careful consideration of the TME and potential off-target effects. Future research should focus on developing targeted delivery systems and combination therapies to maximize the therapeutic potential of TMEM173 activation in cancer treatment.

TMEM176A and TMEM176B, both belonging to the membrane-spanning 4-domains family, have emerged as key regulators of immune responses and cancer progression. TMEM176A is localized on chromosome 7q36.1 and has been identified as a potential tumor suppressor in various types of cancer, including esophageal squamous cell carcinoma (ESCC) and CRC (109). In addition, TMEM176B, also known as tolerance-related and induced, carries out a key role in immune modulation and cancer progression (110).

TMEM176A has been revealed to suppress the growth of ESCC cells both in vitro and in vivo (110-112), suggesting its potential as a diagnostic and prognostic biomarker for ESCC. In ESCC, the loss of TMEM176A expression is associated with promoter hypermethylation (111). TMEM176A promoter methylation occurs in ~66% of primary ESCC tumors, which associates with its reduced expression, poor tumor differentiation, reduced survival rates and aggressive cancer phenotypes (111). The restoration of TMEM176A expression using demethylation agents, such as 5'-aza-2'-deoxycytidine, inhibits cell migration and invasion, thereby promoting apoptosis in ESCC cells and suppressing cancer progression. Additionally, in CRC, TMEM176A promoter methylation is observed in nearly half of the primary tumors, with TMEM176A overexpression resulting in suppressed cell proliferation, migration, invasion and induced apoptosis (112). Notably, TMEM176A is also involved in regulating glioma cell cycles through pathways such as ERK1/2, further validating its role as a tumor suppressor (112). Collectively, these findings establish TMEM176A as a potential tumor suppressor gene, with its expression levels serving as valuable prognostic indicators across multiple cancer types (113).

TMEM176B has been extensively studied in various types of cancer, where it often promotes tumor progression. In CRC, TMEM176B inhibits the NOD-, LRR-, and pyrin domain-containing protein 3 inflammasome, thereby suppressing NK cell activity and promoting EMT, a key process in metastasis. Silencing TMEM176B reduces tumor growth, metastasis and EMT while enhancing apoptosis and immune activation (114). In GC, TMEM176B overexpression drives tumor progression by regulating the PI3K-Akt-mTOR signaling pathway and amino acid metabolism. Its knockdown inhibits cell proliferation, migration and invasion, while promoting apoptosis. Clinically, TMEM176B expression is associated with a worse prognosis, making it a potential prognostic marker (115). TMEM176B also carries out a role in ovarian cancer (OC), where it acts as a tumor suppressor. Its downregulation is associated with increased EMT, proliferation and metastasis, mediated through the Wnt/β-catenin signaling pathway. Restoring TMEM176B expression inhibits these processes, highlighting its therapeutic potential (116).

TMEM176B also carries out a key role in regulating immune responses, especially in DCs (117). TMEM176B is recognized as a key modulator of allograft tolerance and immune system function (117). A study involving autologous tolerogenic DCs (ATDCs) demonstrated that TMEM176B expression in ATDCs was essential for inducing donor-specific immune tolerance and prolonging graft survival (118). TMEM176B-deficient ATDCs failed to cross-present antigens effectively, impairing their ability to induce regulatory CD⁸⁺ T cells and hindering allograft tolerance (118). TMEM176B inhibits inflammasome activation, which dampens anti-tumor immunity. Targeting TMEM176B unleashes inflammasome activity, increasing CD8⁺ T cell-mediated tumor control and enhancing the effects of anti-CTLA-4 and anti-PD-1 therapies (119). These findings underscore the importance of TMEM176B in modulating immune responses, particularly through its influence on antigen cross-presentation and regulation of phagosomal pH, both of which are important for immune tolerance (120). Additionally, TMEM176B has been implicated in regulating immune checkpoint responses, particularly in the context of PD-1 blockade therapy. Elevated TMEM176B expression in tumor stromal cells is associated with a worse prognosis, suggesting that it may act as a negative modulator of anti-tumor immunity (121). Its role in immune evasion has prompted investigations into its potential as a biomarker for predicting patient response to immune checkpoint inhibitors, including anti-PD-1 therapies. TMEM176B negatively regulated the antitumor activity of CD146⁺ TAMs. Inhibition of TMEM176B enhanced TAM-mediated anti-tumor immunity, highlighting a potential immunotherapeutic strategy (122). Thus, as an immune-regulating cation channel, TMEM176B modulates immune cell trafficking and function, further highlighting its potential as a therapeutic target (123).

TMEM176A and TMEM176B are known to physically interact and co-localize at both the plasma membrane and vesicular compartments within immune cells (124). In lymphoma, overexpression of both proteins has been associated with immune evasion, enabling cancer cells to evade immune surveillance and develop resistance to chemotherapy (124,125). This interaction suggested that the two proteins may function synergistically to regulate immune responses and contribute to tumor progression. Both TMEM176A and TMEM176B are downregulated during DC maturation, with their overexpression inhibiting this process and suggesting a role in maintaining an immature state that facilitates immune tolerance (123).

TMEM176A and TMEM176B have emerged as key factors in cancer biology, particularly in immune regulation and tumor suppression. Their roles in immune modulation, especially through the regulation of DC function and antigen cross-presentation, position them as promising targets for novel therapeutic strategies aimed at enhancing immune checkpoint blockade efficacy and improving cancer immunotherapy outcomes. Future research should focus on more comprehensively elucidating the precise molecular mechanisms by which TMEM176A and TMEM176B regulate immune responses and tumor progression. Clinical trials targeting these proteins, either alone or in combination with existing immune checkpoint inhibitors, may provide key insights into their therapeutic potential.

TMEM16 proteins, also known as anoctamins, are a family of ten MPs with various tissue expression and subcellular localization. TMEM16A, also referred to as anoctamin 1 (ANO1), is a calcium-activated chloride channel (CaCC) mapped to chromosome 11q13. It contains eight transmembrane domains and a highly conserved, functionally undefined domain (DUF590), with its expression predominantly observed in secretory epithelial cells, smooth muscle tissue and sensory neurons (126). TMEM16A is acknowledged as a key modulator of tumor progression. It is frequently amplified in a variety of malignancies, including breast cancer, esophageal cancer and head and neck squamous cell carcinomas (HNSCCs), where its expression is associated with a poor prognosis, increased tumor size and advanced clinical stages (127).

TMEM16A carries out a key role in tumorigenesis by activating key signaling pathways, including the EGFR and calcium/calmodulin-dependent protein kinase pathways (128). Silencing of TMEM16A has been revealed to inhibit the proliferation of esophageal and HNSCC cells and induce apoptosis through the MAPK and AKT signaling pathways. TMEM16A is involved in EMT, a key process in cancer metastasis, by regulating the transition from an epithelial to a mesenchymal state, thus enhancing cell migration and invasion (129). In CRC, TMEM16A carries out a key role in disease progression by promoting cell migration and invasion. It activates the Wnt/β-catenin signaling pathway by upregulating key components such as Frizzled protein 1 and β-catenin, while downregulating GSK3β (129,130). The overexpression of TMEM16A is notably elevated in HNSCC, esophageal and prostate cancer, where it is associated with distant metastasis and a poor prognosis (131).

The molecular mechanisms underlying these effects include a role independent of its channel function in promoting cell proliferation. Research suggests that TMEM16A regulates cancer cell growth by interacting with other MPs rather than exclusively through its chloride conductance (131). For example, TMEM16A has been revealed to interact with EGFR, thereby potentiating EGFR signaling in HNSCC cells (128). This interaction not only stabilizes EGFR but also increases TMEM16A protein expression, thereby establishing a feedback loop between TMEM16A and EGFR signaling pathways, which likely contributes to enhanced cancer cell proliferation and survival. Knockdown of TMEM16A has been revealed to reduce myeloid cell leukemia 1 expression and promote the perinuclear redistribution of p27^Kip1, thereby inducing cell cycle arrest, suppressing tumor proliferation and promoting apoptosis (132). However, Shiwarski et al (133) reported that stable reduction of TMEM16A expression enhanced the motility of HNSCC cells and facilitated metastasis, independent of 11q13 amplification. Additionally, TMEM16A overexpression is associated with increased Erk1/2 activity, reduced Bim expression and decreased apoptotic activity, contributing to tumor progression and cisplatin resistance (134). These conflicting findings underscore the multifaceted role of TMEM16A in HNSCC progression. Further studies revealed that TMEM16A expression is associated with tumor subtype: In general, in HNSCC, elevated TMEM16A levels associate with shorter survival and increased risk of distant metastasis (135,136), whereas in human papilloma virus (HPV)-positive HNSCC, its expression was not associated with prognostic significance (136). This suggests that TMEM16A-targeted therapies may be inappropriate for HPV-positive patients. Collectively, these findings indicate that the function of TMEM16A is context-dependent, shaped by the TME and specific cellular subtypes. Continued clinical and molecular investigations are required to clarify its precise role in cancer progression.

TMEM16A has emerged as a potential biomarker for several types of cancer, including esophageal and gastrointestinal squamous cell carcinoma (127). Its expression is associated with clinical staging and disease progression, making it a valuable prognostic indicator. Moreover, TMEM16A functions as a predictor of therapeutic response to EGFR-targeted therapies, particularly in HNSCC, where TMEM16A overexpression may mediate resistance to EGFR inhibitors (137). Given its key role in tumor progression and interaction with EGFR signaling, TMEM16A represents a compelling therapeutic target. Targeting TMEM16A in conjunction with EGFR may offer a strategy to bypass resistance mechanisms and enhance the efficacy of existing EGFR-targeted therapies in cancer treatment (128).

Amplification of chromosome 11q13, where TMEM16A (ANO1) is located, is associated with a poor prognosis in patients with breast cancer. TMEM16A amplification and overexpression are associated with a higher tumor grade and worse outcomes, primarily through activation of EGFR and CaMKII signaling pathways to promote cell proliferation (138). TMEM16A expression also associates with immunohistochemical markers such as β-catenin, cyclin D1 and E-cadherin, and has been identified as an independent prognostic marker (139). Functional studies revealed that TMEM16A inhibition induced G0/G1 cell cycle arrest and reduced the invasiveness of breast cancer cells, underscoring its potential as a therapeutic target (139,140). However, conflicting data regarding its association with hormone receptors (HER2, ER and PR) suggested that the role of TMEM16A may vary across molecular subtypes and cellular contexts (140). Upregulation of TMEM16A is notably associated with CRC progression and higher TNM staging (141). Sui et al (142) confirmed that TMEM16A knockout inhibited the growth, migration and invasion of CRC cells by suppressing the MAPK/ERK signaling pathway. It has been reported that endogenous TMEM16A knockout suppressed CRC cell proliferation and induced apoptosis by inactivating the downstream Wnt/β-catenin signaling pathway (142). Li et al (143) proposed that TMEM16A mRNA expression was associated with lymph node metastasis in CRC and may thus serve as an independent predictive marker for lymphatic involvement. These findings establish the key role of TMEM16A in CRC progression and metastasis. Overexpression of TMEM16A is associated with TNM staging and Gleason scoring in prostate cancer, carrying out a key role in tumor growth, progression and metastasis (144).

Silencing or inhibiting endogenous TMEM16A has been revealed to suppress prostate cancer growth, induce apoptosis and increase TNF-α expression levels (145). Notably, natural products such as resveratrol and luteolin serve both as TMEM16A inhibitors and antitumor agents, effectively reducing prostate cancer cell proliferation and migration (146,147). These findings highlight the therapeutic potential of targeting TMEM16A in prostate cancer treatment. TMEM16A is considerably upregulated in epithelial OC cells, and its upregulation is associated with increased staging and lower differentiation (148). Downregulation of TMEM16A suppressed OC cell growth by reducing PI3K/Akt phosphorylation and disrupting the PI3K/Akt signaling pathway (148). These findings highlight the key role of TMEM16A in OC progression, with its expression associated with advanced disease and a poor prognosis. Given its role in cancer progression, TMEM16A has emerged as a promising therapeutic target. Inhibition of TMEM16A suppresses tumor growth, induces apoptosis and enhances the efficacy of existing therapies (144-149). For example, allicin, a natural compound from garlic, was shown to inhibit the chloride ion current through the TMEM16A channel and exhibit synergistic anticancer effects with cisplatin in lung cancer (149). Similarly, idebenone, a novel TMEM16A inhibitor, can block chloride channel activity and was shown to induce apoptosis in normal prostate and PC cells (150). Furthermore, TMEM16A inhibitors such as T16Ainh-A01 and CaCCinh-A01 have demonstrated efficacy in reducing tumor growth and invasiveness in prostate cancer (144).

TMEM16A, as a CaCC, carries out a key role in calcium-activated chloride secretion, which is involved in the pathogenesis of secretory diarrhea. Yin et al (151) revealed in rotavirus-induced diarrhea that viral enterotoxin NSP4 enhanced intracellular calcium levels, activating TMEM16A-mediated chloride secretion, which, in-turn, contributed to fluid loss and diarrhea. Given that chemotherapy-induced diarrhea in patients with cancer often involves dysregulated epithelial ion transport, TMEM16A may similarly contribute to this adverse effect. Thus, TMEM16A may serve as a mechanistic link between increased chloride secretion and diarrhea in both infectious and iatrogenic contexts.

TMEM16A, through its dual function as both a chloride channel and a signaling modulator, carries out a pivotal role in tumor biology. The regulation of cell proliferation, migration and metastasis by TMEM16A, in addition to its association with EGFR signaling, highlights its potential as both a prognostic biomarker and a therapeutic target for various malignancies.

TMEM45A consists of 275 amino acids, composed of 5-7 transmembrane domains and is primarily localized in the Golgi apparatus (4). It is highly expressed in the skin, where it carries out a key role in epidermal differentiation and keratinization, processes essential for preserving the structural integrity of the skin and barrier function (152). Beyond its role in normal cellular functions, TMEM45A is involved in the pathogenesis of various types of cancer, including gliomas, breast cancer, HCC, RCC and OC, where it is commonly upregulated (153).

TGF-β is a key factor regulating various cellular processes such as proliferation, migration and invasion. In OC, the expression of TMEM45A is closely associated with the activation of the TGF-β signaling pathway. Silencing TMEM45A not only reduced cell proliferation, adhesion and invasion, but also downregulated cancer-promoting factors such as TGF-β1, TGF-β2, RhoA and ROCK2 (154). This association has been revealed to contribute to tumor progression and metastasis and a similar mechanism has been identified in glioma cell lines, providing further evidence for the oncogenic potential of TMEM45A in these cancer types (152,153). Notably, increased TMEM45A expression in breast cancer and cervical cancer (CC) has been associated with poor OS, indicating that TMEM45A could function as an important prognostic biomarker for these malignancies (155).

TMEM45A short hairpin RNA inhibited the proliferation of CC cells, arrested the cell cycle at the S phase and promoted apoptosis. It also suppressed EMT by downregulating Vimentin and N-cadherin, and upregulating E-cadherin, thereby reducing the invasive and migratory ability of the cells. The expression of TMEM45A in cisplatin-resistant cell lines SiHa/DDP and HeLa/DDP was revealed to be increased compared with their parental cells, and inhibiting TMEM45A markedly reduced the IC₅₀ of these resistant cells to cisplatin. Silencing TMEM45A inhibited the proliferation, invasion, migration and EMT of HPV-positive CC cells, regulated cell cycle distribution and promoted apoptosis (156). Sun et al (153) revealed that TMEM45A was overexpressed in glioma tissues compared with non-tumorous brain tissues. TMEM45A mRNA levels progressively increased with higher histological grades of glioma and were associated with shorter survival times of patients. Knockout of TMEM45A in glioma cell lines markedly inhibited cell proliferation and induced G1 phase arrest, and reduced the migratory and invasive abilities of glioma cells. Notably, treatment with TMEM45A small interfering (si)RNA downregulated key proteins involved in cell cycle progression (Cyclin D1, CDK4 and proliferating cell nuclear antigen) as well as invasion-related proteins (MMP-2 and MMP-9), providing a potential mechanistic explanation for its role in glioma.

TMEM45A is closely associated with intratumoral heterogeneity, a major challenge in cancer treatment. In lung adenocarcinoma, TMEM45A was revealed to be overexpressed in tumor tissues compared with healthy tissues, and its expression was associated with markers such as GLUT1, MCT4 and CA9, which are associated with a hypoxic microenvironment and altered metabolism (157). Similarly, in ccRCC, TMEM45A upregulation associated with poor OS, disease-free survival and advanced clinicopathological features such as higher histological grade and TNM stage (158).

TMEM45A is a multifunctional protein associated with tumorigenesis, chemotherapy resistance and fibrosis. Its ability to modulate key signaling pathways, including TGF-β and Notch, positions it as a promising candidate for therapeutic targeting. In GC, increased TMEM45A expression was associated with poor prognosis and immune cell infiltration, making it a potential independent prognostic marker (159). In breast cancer, TMEM45A expression is associated with poor survival and resistance to CDK4/6 inhibitors such as palbociclib, further underscoring its prognostic value (160). Furthermore, the association of TMEM45A with a poor prognosis in various types of cancer and its involvement in MDR highlights its potential as a biomarker for cancer progression and therapeutic resistance (155,161,162). In breast cancer, engineered exosomes loaded with siRNA targeting TMEM45A restored sensitivity to palbociclib and suppressed tumor growth (160). Similarly, in CC, TMEM45A knockdown reversed cisplatin resistance and inhibited proliferation, migration and EMT in HPV-positive cell lines (156). Future research focusing on the molecular mechanisms underlying the functions of TMEM45A in these contexts are essential for the development of targeted therapies aimed at overcoming resistance and improving patient outcomes.

TMEM45B has attracted considerable attention due to its involvement in various types of cancer, including lung cancer, PC and GC (163). Okada et al (163) have highlighted that TMEM45B as an oncogene that plays a pivotal role in cancer pathogenesis by regulating essential cellular processes, including proliferation, invasion, migration, and apoptosis.

In lung cancer, TMEM45B overexpression is associated with poor patient survival. Knockdown of TMEM45B reduced cell proliferation, induced cell cycle arrest and apoptosis, and inhibited cell migration and invasion. These effects were mediated through the regulation of cell cycle-related proteins (CDK2 and CDC25A), apoptosis-related proteins (Bcl2 and Bax) and metastasis-related proteins (MMP-9, Twist and Snail). TMEM45B may thus serve as a potential prognostic marker and therapeutic target in lung cancer (164). TMEM45B is highly expressed in PC tissues and cell lines. Its knockdown inhibited cell proliferation, invasion and migration while inducing cell cycle arrest and apoptosis. Conversely, TMEM45B overexpression promoted these processes and inhibited apoptosis. Gene set enrichment analysis revealed that TMEM45B regulated genes that are involved in the cell cycle and metastasis pathways, further supporting its oncogenic role in PC (165). Shen et al (166) also demonstrated that in GC, TMEM45B was overexpressed in both tissues and cell lines. Silencing TMEM45B inhibited cell proliferation, migration, invasion and EMT. This suppression was mediated through the inhibition of the JAK2/STAT3 signaling pathway, as evidenced by reduced levels of phosphorylated JAK2 and STAT3 upon TMEM45B knockdown (166).

Moreover, in osteosarcoma, Li et al (167) verified the upregulation of TMEM45B expression and revealed that its knockdown in U2OS cells effectively suppressed proliferation, migration and invasion in vitro, and inhibited tumor growth in xenograft models. This effect was associated with the downregulation of key proteins such as β-catenin, cyclin D1 and c-Myc, which are important for cancer cell proliferation and metastasis (167). These findings collectively indicate that TMEM45B is a potent regulator of tumorigenesis across various cancer types. Its dysregulated expression may act as a potential prognostic biomarker for cancer progression and it holds promise as a therapeutic target. Furthermore, previous studies have demonstrated that the regulatory effects of TMEM45B extend to modulating the TME, influencing immune responses and potentially modulating the response to chemotherapeutic agents (167,168). Similarly, TMEM45B has been identified as a novel predictive biomarker for prostate cancer progression and metastasis. Its expression is notably increased in tumor cell lines with high metastatic potential and is associated with biochemical recurrence, distant metastasis and a poor OS. Multivariate analysis confirmed that TMEM45B was an independent risk factor for metastasis, making it a promising prognostic marker for patients with prostate cancer (169).

TMEM45B exerts its oncogenic effects through multiple signaling pathways, including Wnt/β-catenin, JAK2/STAT3 and TGF-β. It regulates key cellular processes such as proliferation, apoptosis, migration and invasion by modulating the expression of downstream target genes and proteins. Additionally, the involvement of TMEM45B in EMT and chemotherapy resistance further underscores its role in cancer progression. Given its central role in regulating key pathways involved in cancer progression, TMEM45B may be developed as a targeted therapy, thereby improving patient outcomes.

TMEM48 is a member of the nuclear pore complex (NPC) family of proteins and is essential for maintaining nuclear membrane integrity and enabling nuclear transport (170). The protein consists of six transmembrane domains and is vital for NPC assembly, which is important for regulating several cellular processes, including chromosome segregation, gene transcription, DNA replication, DNA damage repair and apoptosis (170,171). Alterations in the expression of NPC proteins, including TMEM48, have been associated with the onset and progression of various malignancies, such as breast, melanoma, pancreatic, colon, gastric, prostate, esophageal, lung cancer and lymphoma (170-172).

Previous studies have highlighted the involvement of TMEM48 in NSCLC (170-173). Qiao et al (173) demonstrated that TMEM48 expression was markedly increased in NSCLC tissues compared with adjacent normal tissues. This overexpression was associated with a poor prognosis, including reduced survival times, increased tumor size and lymph node metastasis. TMEM48 regulates essential cellular processes, such as proliferation, migration and invasion, by regulating genes involved in the cell cycle and DNA replication. Knockdown of TMEM48 in NSCLC cell lines led to reduced cell proliferation, induction of G1 phase cell cycle arrest and inhibition of migration and invasion. Furthermore, silencing of TMEM48 triggered apoptosis in NSCLC cells. In an in vivo study, silencing TMEM48 led to a notable reduction in tumor weight in xenograft models (173).

Moreover, the study by Akkafa et al (6) suggests that microRNA (miR)-421, an miR targeting TMEM48, potentiates apoptotic signaling pathways in NSCLC. Suppression of TMEM48 by miR-421 upregulated the expression of apoptosis-related proteins, such as caspase-3, PTEN and p53, which collectively promote cell death. This indicated that targeting TMEM48 may serve as a therapeutic strategy for improving the efficacy of treatments in NSCLC. TMEM48 has been identified in other types of cancer, such as CC (174). In CC, TMEM48 is overexpressed and its knockdown inhibited cell proliferation, migration and invasion both in vitro and in vivo (174). Jiang et al (174) indicated that TMEM48 promotes CC progression by activating the Wnt/β-catenin signaling pathway, as evidenced by the reduced expression of β-catenin, TCF1 and AXIN2 following TMEM48 knockdown. This suggested that TMEM48 is important in tumorigenesis by modulating key signaling pathways involved in cancer progression.

TMEM48 is a promising prognostic marker and therapeutic target. Given its central role in regulating cellular functions key for tumor progression, TMEM48 represents a valuable target for future therapeutic strategies focused on inhibiting cancer growth and metastasis. Further research is needed to explore the therapeutic potential of TMEM48 in various malignancies, including its modulation by miRNAs.

TMEM65 is a mitochondrial inner membrane protein whose deficiency has been implicated in a mitochondrial disorder characterized by a complex encephalomyopathic phenotype (175,176). Clinical manifestations include microcephaly, craniofacial dysmorphism, psychomotor regression, generalized hypotonia, growth retardation, lactic acidosis, intractable seizures and dyskinetic movements, notably in the absence of cardiomyopathy (175). Previously, TMEM65 has emerged as a pivotal factor in cancer biology, with its involvement reported across various malignancies, including CRC, TNBC, GC and HCC (175-180). TMEM65 carries out a multifaceted role in tumorigenesis by modulating mitochondrial dynamics, driving metabolic reprogramming and regulating signaling pathways associated with cancer progression and therapeutic resistance. This contrast between its role in congenital mitochondrial disease and acquired malignancies underscores its biological value and potential as a therapeutic target.

In CRC, TMEM65 is transcriptionally regulated by the CHD6-TCF4 axis, which is activated by both EGF and Wnt signaling pathways. CHD6, a chromatin remodeler, binds to Wnt signaling transcription factor TCF4 to facilitate TMEM65 expression. This axis promotes mitochondrial dynamics and ATP production, essential for cancer cell proliferation, migration and invasion. Targeting the CHD6-TMEM65 axis with Wnt inhibitors and anti-EGFR therapies showed promise in restricting CRC growth (176). TMEM65 acts as an oncogene in TNBC, where it was revealed to be upregulated by the transcription factor MYC and DNA demethylase TET3. TMEM65 enhanced mitochondrial oxidative phosphorylation and reactive oxygen species production, which, in turn, activates hypoxia inducible factor (HIF)-1α and SERPINB3 and promotes cancer stemness, progression, and cisplatin resistance. Inhibition of MYC and TET3 attenuated TMEM65-driven TNBC progression, highlighting its potential as a therapeutic target (177). TMEM65 amplification and overexpression are common in GC and are associated with a poor prognosis. TMEM65 promoted tumorigenesis by activating the PI3K-Akt-mTOR signaling pathway through its interaction with YWHAZ, a protein that inhibits ubiquitin-mediated degradation. Silencing TMEM65 suppresses tumor growth and metastasis, making it a promising therapeutic target in GC (163). In HBV-related HCC, TMEM65 amplification was driven by HBV integration-induced genomic rearrangements. TMEM65 contributes to tumorigenesis by promoting mitochondrial function and metabolic reprogramming, which are key for cancer cell survival and proliferation (178).

TMEM65 expression is associated with tumor immune infiltration, particularly CD8⁺ T effector cells and immune checkpoint markers. Its role in modulating the TME and immune response makes it a potential biomarker for predicting prognosis and the efficacy of immunotherapy (179). TMEM65 may serve as a target for chimeric antigen receptor T-cell therapies and antibody-drug conjugates. Its overexpression in cancer tissues and low expression in normal tissues make it an attractive candidate for immune-based interventions (180). TMEM65 is a pivotal oncogene that drives cancer progression through its roles in mitochondrial dynamics, metabolic reprogramming and signaling pathway activation. Its overexpression is associated with poor prognosis across multiple cancer types, making it a promising biomarker and therapeutic target. Future research should focus on developing targeted therapies that exploit the oncogenic function of TMEM65 while minimizing off-target effects.

TMEM140, also known as FLJ11000, is a TP encoded by a gene located on chromosome 7q33, consisting of 185 amino acids (181). Although initially identified for its role in supporting hematopoietic stem cells in vitro (181-183), TMEM140 has since been associated with various biological processes, including tumorigenesis and viral infection (182). Guan et al (183) have highlighted the dual functions of TMEM140 as both a prognostic biomarker and a potential therapeutic target in cancer and its role in inhibiting herpes simplex virus 1 (HSV-1) replication. TMEM140 has emerged as a key player in various types of cancer, including gliomas and GC. Gliomas are among the most common and aggressive primary brain tumors, characterized by a poor prognosis and limited treatment options. TMEM140 is overexpressed in gliomas compared with normal brain tissues and its high expression is associated with a larger tumor size, higher histologic grade and shorter OS (181). An In vitro study using glioma cell lines have revealed that silencing TMEM140 inhibited cell proliferation, migration and invasion, with concurrent arrest in the G1 phase of the cell cycle and activation of apoptotic pathways (181). It regulates cell cycle progression by shortening the cell cycle and reducing apoptosis, thereby promoting tumor cell proliferation. Additionally, TMEM140 enhanced tumor cell adhesion and survival by modulating the expression of adhesion and anti-apoptotic proteins (181-183). In vivo silencing of TMEM140 led to a marked reduction in tumor volume and weight (183), highlighting its pivotal role in tumor growth. These findings identify TMEM140 as a novel prognostic biomarker and therapeutic target for gliomas, underscoring its potential for clinical application in glioma treatment. Beyond gliomas, TMEM140 has been implicated in other cancer types through its co-expression with long-chain acyl-coenzyme A synthetase 5 and this was predictive of improved prognosis in breast, ovarian and lung cancer (184). This suggests that TMEM140 may carry out a context-dependent role in cancer progression, potentially acting as a tumor suppressor in certain malignancies (184). Furthermore, TMEM140 has been identified as a candidate gene in HTLV-1-infected cancer cells, indicating its broader relevance in cancer biology (185).

TMEM140 is a multifunctional protein that is involved in several processes in cancer biology, autoimmune diseases and viral infections. In systemic sclerosis, the involvement of TMEM140 in DNA methylation changes indicates a potential key role in disease pathogenesis, particularly in fibroblast function (186). Additionally, its role in inhibiting HSV-1 replication highlights its promise as an antiviral target. Given its diverse functions, TMEM140 may serve as a compelling candidate for further investigation, with implications for therapeutic strategies across a variety of diseases.

TMEM158, located on chromosome 3p21.3, also known as BBP, Ras-induced senescence 1 protein, p40BBP and HBB, was initially recognized as an upregulated potential tumor suppressor gene in the context of Ras V12 lentiviral infection-induced senescence in fibroblasts (187). Li et al (188) have highlighted its key role in the development of various types of cancer. Importantly, TMEM158 is overexpressed in Wilms tumor (nephroblastoma), with somatic mutations in the β-catenin gene, indicating a connection between Ras and Wnt signaling pathways (189). In lung cancer, TMEM158 is highly expressed in advanced-stage tumors and is associated with poor OS (61). It promotes EMT and enhanced cell migration, contributing to aggressive tumor behavior (61). Additionally, TMEM158 expression is induced under hypoxic conditions in a HIF-1α-dependent manner, associating it with tumor hypoxia, a hallmark of cancer progression (61). Moreover, TMEM158 has emerged as a potential biomarker for predicting the efficacy of cisplatin-based therapy in NSCLC, with its expression correlating with improved therapeutic outcomes (61,190).

In PC, TMEM158 overexpression promotes cell proliferation, migration and invasion through the activation of the TGFβ1 and PI3K/AKT signaling pathways, highlighting its oncogenic potential (191). TMEM158 is amplified in GC tissues and is associated with poor prognosis (192). In GC, it was revealed to accelerate GC cell proliferation by activating the PI3K/AKT signaling pathway and its knockdown inhibited tumor growth, suggesting its potential as a biomarker and therapeutic target (192). In CRC, downregulation of TMEM158 expression notably impairs tumor cell proliferation, migration and MDR, highlighting its value in both tumor progression and chemoresistance (193). Furthermore, TMEM158 is involved in regulating EMT in various types of cancer, enhancing metastasis and aggressiveness. In OC, TMEM158 expression was shown to be considerably upregulated, thereby promoting tumorigenic properties, including cell proliferation, invasion, adhesion and migration (194). Silencing TMEM158 resulted in downregulation of intercellular adhesion molecules (ICAM1 and VCAM1) and disruption of the TGF-β signaling pathway, further emphasizing its role as an oncogene (194). It also contributed to doxorubicin resistance by upregulating ABCG2, a drug efflux transporter (195). TMEM158 is highly expressed in TNBC and was shown to be associated with poor clinical outcomes and to drive EMT and tumor metastasis via activation of the TGF-β signaling pathway, highlighting it as a potential therapeutic target for this aggressive breast cancer subtype (196).

In glioblastoma (GBM), overexpression of TMEM158 was associated with a poor prognosis, whereas silencing it suppressed cell migration and invasion by interfering with STAT3 signaling pathways (188). Unlike its oncogenic role in other types of cancer, TMEM158 is downregulated in prostate cancer and is associated with advanced disease features and poor survival. Its expression is negatively regulated by androgen receptor signaling, and it may carry out a tumor-suppressive role in this context (197,198). Additionally, TMEM158 was shown to be involved in immune modulation, correlating with tumor mutational burden, microsatellite instability and immune cell infiltration in the TME (190,197,198).

In NSCLC, TMEM158 is considered to modulate immune checkpoints, thereby enhancing the therapeutic efficacy of immune checkpoint inhibitors such as anti-PD-1 and anti-CTLA-4 (190,197,198). This emerging role in immuno-oncology highlights a promising avenue for therapeutic interventions targeting TMEM158. Additionally, pan-cancer analyses demonstrated that TMEM158 is upregulated in a range of cancer types, including melanoma and HCC, where its elevated expression is associated with tumor aggressiveness and poor prognosis (197). In these contexts, TMEM158 has been implicated in hypoxia-induced pathways, thus facilitating tumor growth in hypoxic conditions. These findings collectively highlight the key role of TMEM158 in regulating tumor progression, metastasis, immune evasion and chemoresistance across various cancer types. Its involvement in signaling pathways, including TGFβ, PI3K/AKT, STAT3 and Wnt, as well as its potential in immune modulation, establishes TMEM158 as both a prognostic biomarker and a promising therapeutic target in oncology.

TMEM159, also known as promethin, is a small TP consisting of 161 amino acids with four adjacent transmembrane helices forming two helical hairpins (199). It carries out a key role in lipid droplet (LD) biogenesis through its interaction with Seipin, a key regulator of lipid storage in the ER (200). The TMEM159-Seipin complex co-purified with triacylglycerol and facilitated the initiation of LD formation. Upon maturation of LD, TMEM159 dissociated and relocated to the LD surface, thereby participating in the maintenance of lipid homeostasis (200).

Although extensively studied in the context of lipid metabolism, TMEM159 has recently gained attention for its potential involvement in cancer progression (199-202). Notably, in GBM, enhanced LD formation, which is associated with a poor prognosis under metabolic stress, has been associated with altered TMEM159 expression (201). TMEM159 may contribute to glioma malignancy by modulating EGFR signaling pathways, which are important for cancer cell proliferation, migration and survival (201). These findings suggest that TMEM159 could serve as both a molecular biomarker and therapeutic target in lipid-associated malignancies such as GBM (201,202).

Beyond cancer, TMEM159 has also been associated with neuropsychiatric disorders through genome-wide association studies (199-205), but its mechanistic involvement in tumorigenesis, particularly through pathways associated with lipid regulation and oncogenic signaling, may represent promising directions for future cancer-focused research. Continued investigation is warranted to fully elucidate the multifaceted role of TMEM159 in lipid metabolism and cancer biology (203-205).

TMEM205 is a TP encoded by a gene located on chromosome 19p13.2, and is formed of 189 amino acids. TMEM205 has emerged as a notable player in cancer biology, particularly in the context of drug resistance, tumor progression and immune modulation. TMEM205 has shown promise as a biomarker for chemoresistance and prognosis. In high-grade serous OC, TMEM205 was found to be differentially expressed in extracellular vesicles derived from platinum-resistant patients with OC, demonstrating high diagnostic accuracy for platinum resistance (206). In HCC, low TMEM205 expression was independently associated with poor OS and disease-specific survival, highlighting it as a potential prognostic marker (207). TMEM205 is associated with chemoresistance, particularly to platinum-based therapies such as cisplatin (208). Moreover, TMEM205 was also shown to carry out a role in tumor progression and immune evasion (208). Targeting TMEM205 may offer a novel strategy to overcome chemoresistance and improve treatment outcomes. In ovarian clear cell carcinoma, the combination of oncolytic viruses and cisplatin reduced TMEM205 expression and sensitized cells to chemotherapy (208). Similarly, small molecule inhibitors such as L-2663 have shown efficacy in enhancing platinum sensitivity in OC (209). These findings underscore the potential of TMEM205 as a therapeutic target in combination therapies.

TMEM205 is a multifaceted protein involved in chemoresistance, tumor progression and immune modulation across various types of cancer. Its upregulation is associated with poor treatment outcomes, while its inhibition enhances chemotherapy efficacy. As a biomarker, TMEM205 may serve as a diagnostic and prognostic value, particularly in various types of platinum-resistant cancer (206-209). Future research should focus on developing targeted therapies to modulate TMEM205 activity, potentially improving patient outcomes in various types of resistant cancer.

The TME, composed of immune cells, stromal components, extracellular matrix and soluble factors, carries out a pivotal role in cancer progression, immune evasion and therapy response. Growing evidence shows that TPs not only regulate tumor cell behavior but also engage in bidirectional crosstalk with the TME, contributing to its remodeling and tumor development (4,5).

Several TMEM proteins have been shown to regulate tumor-immune interactions. For example, TMEM173 carries out a key role in the activation of innate immune responses and can modulate T-cell infiltration and antitumor immunity within the TME (210-212). Evidence from several types of cancer, including SCLC, TNBC, CC and GBM, demonstrates that activation of the cGAS-STING pathway can reshape the TME by promoting chemokine production (such as CXCL10 and CCL5), increasing CD8⁺ T cell infiltration and potentiating antitumor immunity (210,212-214). Microbiota-derived STING agonists can reprogram monocytes and DC in the TME, enhancing IFN-I production and improving the efficacy of immune checkpoint blockade (215). Moreover, STING signaling can be triggered not only by endogenous cytosolic DNA but also by tumor-derived exosomes, indicating a dynamic extracellular-intracellular feedback loop that facilitates immune regulation (213). STING was also shown to contribute to immunosuppression in certain contexts, such as by promoting regulatory T cell (Treg) differentiation or inducing ER stress and T cell apoptosis through non-canonical pathways (213,216). Senescent tumor cells release mitochondrial DNA that activates the cGAS-STING pathway in myeloid-derived suppressor cells, promoting immunosuppression and tumor progression (107). These multifaceted roles highlight TMEM173 as a key modulator of immune surveillance and tumor progression, reflecting the complex bidirectional communication between TMEM proteins and the TME.

TMEM205 carries out a key role in modulating TME and influencing cancer progression. In HCC, TMEM205 expression was shown to be associated with the immune landscape of the tumor, where low TMEM205 expression was associated with a poor prognosis and survival outcomes (207,209). TMEM205 interacted with various immune cell populations in the TME, particularly macrophages and Tregs (207,209). The expression of TMEM205 was positively associated with the proportion of macrophages, including M1 macrophages, while it was negatively associated with immunosuppressive M2 macrophage markers and Treg markers. This suggested that TMEM205 may exert its antitumor effects by reducing the levels of immunosuppressive cells such as M2 macrophages and Tregs, while promoting the infiltration of cytotoxic CD8⁺ T cells into the TME. Therefore, extracellular feedback through TMEM205 may regulate immune cell infiltration, enhancing antitumor immunity and potentially improving therapeutic responses, especially in combination therapies targeting immune checkpoints (207,209).

TMEM16A also carries out a key role in shaping the TME. In PC, high TMEM16A expression is associated with an immunosuppressive TME, characterized by increased cancer-associated fibroblasts (CAFs) and reduced CD8⁺ T cell infiltration (217). Similarly, in gastrointestinal cancer, TMEM16A contributed to immunotherapy resistance by inhibiting cancer ferroptosis and recruiting CAFs, thereby impairing CD8⁺ T cell-mediated anti-tumor immunity (218). TMEM101 also carried out a key role in modulating the HCC TME and influencing HCC progression. In HCC, TMEM101 expression was markedly upregulated, and was associated with a poor prognosis and advanced tumor grade and stage (219). TMEM101 was shown to interact with various immune cell populations within the TME, particularly influencing macrophage infiltration and T cell activity. High TMEM101 expression is associated with increased M0 macrophage infiltration, which are pro-tumorigenic and decreased infiltration of anti-tumor immune cells such as M1 macrophages and resting memory CD4⁺ T cells. This shift in immune cell populations suggests that TMEM101 promotes tumor progression by modifying the immune landscape in favor of tumor growth. Furthermore, intracellular feedback regulation by TMEM101 was shown to impact pathways related to cell cycle, DNA replication and repair, facilitating tumor proliferation and survival (219). Thus, TMEM101 not only serves as a diagnostic and prognostic biomarker for HCC but also acts as an oncogene that influences the TME, contributing to HCC initiation and progression (219).

TMEM proteins also mediate extracellular and intracellular feedback regulation. Extracellularly, they can interact with cytokines, growth factors and adhesion molecules, modulating upstream signaling events. TMEM52B is a novel regulator that modulates the activity of both E-cadherin and EGFR, exhibiting tumor suppressor-like functions. Lee et al (220) revealed that peptides derived from the extracellular domain (ECD) of TMEM52B considerably inhibit cancer cell survival, invasion and anchorage-independent growth, while reducing the phosphorylation of ERK1/2 and AKT. These peptides stabilize E-cadherin at cell-cell junctions, leading to decreased β-catenin activity, and directly bind to the E-cadherin ECD to block the interaction between soluble E-cadherin and EGFR, thereby suppressing EGFR activation. These findings suggest that TMEM52B ECD-derived peptides not only possess strong anti-cancer potential but also serve as valuable tools for investigating the regulatory role of TMEM52B in the crosstalk between E-cadherin and EGFR (220). Intracellularly, TMEM proteins often participate in key oncogenic pathways such as MAPK, PI3K/AKT and Wnt, forming regulatory loops that either amplify or attenuate cellular responses to environmental cues. These feedback mechanisms may affect cell proliferation, apoptosis, migration and ultimately, cancer progression (4,5,220).

Collectively, the bidirectional interaction between TMEM proteins and the TME contributes to tumor plasticity, immune evasion and chemoresistance. Although this area remains underexplored, it represents a promising direction for future research. An improved understanding of how TMEM proteins influence the TME may lead to the identification of novel therapeutic targets and strategies to modulate tumor-host interactions.