Head and neck squamous cell carcinoma (HNSCC) is the most common malignant tumor in the head and neck region, representing a major public health challenge worldwide. According to the GLOBOCAN 2020 statistical report, HNSCC accounts for over 830,000 new cases and 430,000 deaths annually worldwide, ranking seventh globally in both incidence and mortality rates [1]. Regions in Southeast Asia exhibit a particularly high incidence. In 2022, China recorded over 140,000 new cases, resulting in 80,500 deaths—accounting for 3.1% of all cancer fatalities and ranking seventh among all cancer types [2]. Early symptoms of HNSCC lack specificity, resulting in the majority of patients being diagnosed with locally advanced or metastatic disease. Furthermore, 50% - 60% of HNSCC patients experience recurrence or distant metastasis within two years [3]. Consequently, HNSCC patients face an extremely poor prognosis, with a five-year survival rate below 50%. Surgery, radiotherapy, and platinum-based chemotherapy often carry severe side effects such as dysphagia and organ dysfunction, significantly impairing patients’ quality of life [4]. The advent of targeted therapies and immune checkpoint inhibitors has expanded treatment options for HNSCC, achieving durable responses in some patients. However, these therapies demonstrate limited efficacy in recurrent or metastatic cases [5]. Consequently, identifying safer and more effective therapeutic targets, along with biomarkers for accurate response prediction, holds significant importance.

Calcium ion channels participate in the pathological processes of various diseases, and their abnormal expression and dysfunction are closely associated with tumors. Consequently, targeting these channels with calcium channel blockers has emerged as a promising therapeutic strategy for cancer management. Current pharmacological development in this area primarily focuses on two major classes: transient receptor potential (TRP) channels and voltage-gated calcium channels (VGCC/Cavs) [6]. TRP channels belong to the cellular membrane calcium transport system, which are expressed in normal epithelial cells. They promote uncontrolled proliferation, abnormal differentiation, and impaired apoptosis, leading to uncontrolled cancer spread and tumor invasion [7]. Experimental studies have confirmed the oncogenic role of TRP channels in various cancers, including melanoma, glioblastoma, prostate cancer, and breast adenocarcinoma [8]. Among TRP channel subfamilies, Transient Receptor Potential Melastatin (TRPM) channels constitute the largest group. They act as crucial cellular sensors and signal transducers, finely regulating intracellular and extracellular ion homeostasis [9]. Recent studies have demonstrated the immense potential of the TRPM family in HNSCC diagnosis, prognosis, and therapeutic approaches. This article briefly outlines the composition and physiological functions of TRPM family members, systematically elucidates their mechanisms of action and latest findings in HNSCC development, and explores current clinical applications and challenges associated with TRPM.

The TRPM family comprises non-selective calcium channels, consisting of TRPM1 through TRPM8. Each member contains three domains: an N-terminal region, a transmembrane TRPM domain (TMD), and a C-terminal region. The N-terminal domain contains four Melastatin Homology Regions (MHRs) that sense external stimuli. The transmembrane region S4 serves as the voltage-sensing domain, while the P-loop between S5 and S6 forms the ion channel pore [10]. All TRPM proteins function as cation channels. Most are calcium-permeable (except TRPM4/5), enabling them to influence diverse signaling pathways by modulating cytosolic calcium levels. The C-terminal domains of different members exhibit significant structural variation, but all contain highly conserved TRP box sequences and coiled-coil domains, the latter playing a crucial role in polymer complex formation [11]. Different members participate in distinct physiological and pathological processes. TRPM1 channels are critical for normal melanocyte pigmentation, are expressed in melanocytes and the retina, and are associated with melanoma. TRPM2 senses oxidative stress and is closely linked to diabetes and inflammatory neurodegenerative diseases. TRPM3 participates in pain and temperature perception. TRPM4 and TRPM5 are involved in taste transduction. TRPM6 and TRPM7 regulate magnesium homeostasis. TRPM7 features a unique α-kinase domain at its C-terminus, which phosphorylates the myosin IIA heavy chain to regulate cytoskeleton and focal adhesion dynamics, thereby driving cell migration. In TRPM8, the S5-S6 pore region serves as the binding site for menthol, while the C-terminal domain is involved in temperature sensing and interactions with signaling molecules such as PIP₂. TRPM8 detects cold sensation, responds to menthol stimulation, and serves as a key target in prostate cancer [12]. Additionally, TRPM channels influence tumor progression through microenvironment sensing, signaling pathway interactions, and autophagy regulation [13].

While the roles of TRPM3 and TRPM5 remain less explored, the remaining members exhibit differential expression in HNSCC. For instance, TRPM1 mRNA levels are significantly downregulated in HNSCC tissues [14]. Research indicates that upregulation of miR-211 within the sixth intron of the TRPM1 gene and downregulation of TGFβRII are closely associated with poor prognosis in HNSCC. Functionally, miR-211 promotes HNSCC progression by directly targeting TGFβRII through the miR-211-TGFβRII-c-Myc axis [15]. As a potential therapeutic target, TRPM1 downregulation may be implicated in HNSCC tumorigenesis or progression, though specific mechanisms require further validation. Radiotherapy for head and neck cancer frequently causes irreversible salivary gland damage, severely compromising patients’ quality of life. Radiation mediates irreversible salivary gland injury via the PARP1-ADPR-TRPM2 pathway. Targeting this pathway (via gene knockout, 3-AB, or TPL) significantly restores secretory function, offering a potential therapeutic strategy for head and neck cancer radiotherapy patients [16]. TRPM4, recently identified as a key player in necrosis induced by sodium overload (NECSO), is highly expressed in HNSCC tumor tissues [17]. ROC curve analysis demonstrated moderate diagnostic value of TRPM4 for HNSCC. Co-localization of TRPM4 with integrin α2β1 (ITGA2) synergistically aids HNSCC cells in resisting cell death induced by osmotic rupture and sodium-dependent cell death [18]. TRPM7 is overexpressed in nasopharyngeal carcinoma, laryngeal carcinoma, and hypopharyngeal carcinoma. Qiao et al. demonstrated that salivary magnesium activates the AKT/mTOR pathway via TRPM7 channels to promote HNSCC progression, while TRPM7 inhibitors (e.g., FTY720) block magnesium’s oncogenic effects [19]. Additional studies revealed that TRPM7 promotes metastasis, stem cell properties, and cisplatin resistance in HNSCC through the calcineurin/NFAT pathway. Silencing TRPM7 significantly suppressed these malignant phenotypes and enhanced chemotherapy efficacy in vitro and in vivo [20]. This supports TRPM7 as a novel therapeutic target, with its inhibitors potentially improving HNSCC patient prognosis. The research highlights the potential of ion channels in cancer treatment. A study analyzed that patients with high TRPM8 expression exhibited significantly reduced survival rates, positively correlated with histological grade and lymph node metastasis. Cancer tissues from drinkers or smokers exhibited significantly higher TRPM8 expression than adjacent non-cancerous tissues. In vitro experiments showed that betel nut alkaloid treatment of betel-chewed OSCC cells (SAS, OECM-1) significantly increased TRPM8 mRNA and protein expression [21]. This indicates TRPM8 plays a key role in HNSCC malignant progression and metastasis. Risk factors such as alcohol, tobacco, and arecoline may promote HNSCC development by upregulating TRPM8 expression. However, the molecular mechanisms of TRPM8 in HNSCC remain unclear. Owing to the anatomical and physiological complexity of the head and neck region, HNSCC exhibits considerable heterogeneity depending on the site of origin. The roles of TRPM channels across different HNSCC subsites and their underlying mechanisms are summarized in Table 1.

In summary, the TRPM family participates in the development and progression of HNSCC through multiple mechanisms. TRPM channels show considerable promise as tools for prognostic assessment and as potential therapeutic targets in HNSCC. In prognosis, researchers have established TFBS (TRPC1/3/6 + TRPV2/4 + TRPM8) as an independent prognostic biomarker for HNSCC, reflecting tumor immune status and key oncogenic pathways, though further external validation is warranted [39]. For therapeutic targets, the TRPM8 modulator D3263 has entered Phase I clinical trials for the treatment of prostate cancer [40]. However, most TRPM targets in HNSCC remain confined to in vitro experiments, and translating basic research into clinical applications faces significant challenges.

A primary obstacle is therapeutic specificity, TRPMs are widely distributed throughout the human body, and inhibition may induce toxic side effects, compromising drug efficacy and accuracy. Developing targeted delivery is crucial to addressing this issue. Approaches include exploring antibody-drug conjugates (ADCs), prodrug systems, or nanocarriers, as well as leveraging the tumor microenvironment or tumor-specific antigens for targeted delivery. Furthermore, the functional complexity of TRPM channels presents another layer of difficulty. The same TRPM member may perform opposing roles across different cancers or even at distinct stages of the same cancer. For instance, TRPM2 acts as a tumor suppressor in early-stage oral squamous cell carcinoma but may promote tumor progression in advanced stages. Finally, HNSCC exhibits diverse signaling pathways, and single-targeted TRPM channel inhibition may trigger compensatory mechanisms. Consequently, combination therapies that integrate TRPM modulation with conventional modalities like radiotherapy, chemotherapy, molecularly targeted agents, or immune checkpoint inhibitors hold synergistic potential to overcome this adaptability and improve outcomes. Despite these challenges, advancing research into the biological functions of the TRPM family and technological advancements hold promise for targeted TRPM channel therapies to deliver novel breakthroughs in cancer treatment.

*Corresponding author.