TRPA1, the only member of the ankyrin subfamily, is a polymodal channel that can be activated by a wide variety of noxious external stimuli, such as irritants, often associated with pain and inflammation, and intense cold [60,61,62,63]. TRPA1 can also be gated by several endogenously produced reactive chemical species, including oxidative stress by-products, such as ROS, reactive nitrogen (RNS), and carbonylic (RCS) species [45,62]. TRPA1 is predominantly expressed in the primary sensory neurons of the dorsal root (DRG), vagal (VG), and trigeminal (TG) ganglia, where it signals diverse pain stimuli [64,65,66,67,68]. TRPA1 expression has also been reported in non-neuronal cells, including the mouse inner ear and the organ of Corti [69], vascular endothelial cells [70], enterochromaffin cells of the respiratory tract [60,71], keratinocytes and melanocytes, synoviocytes, and dental pulp and gingival fibroblasts [72,73], as well as mast cells, epithelial, and pancreatic β cells [74,75,76,77,78,79,80,81]. More recently, the presence of TRPA1 in glial cells, such as astrocytes [82], oligodendrocytes [83], and Schwann cells [84,85], has been reported. In addition, the expression of TRPA1 has been observed in different cancer cells, including pancreatic adenocarcinoma and melanoma cells [86,87].

In cancer, TRPA1 activation in prostate tumor endothelial cells acts as a modulator of angiogenesis, since its activation promotes neovascularization, endothelial cell migration, and tubulogenesis in vitro in models of human prostate cancer [88]. TRPA1 activation in lung epithelial cancer cells (A549) can induce a decrease in cell invasion by inhibiting the cyclooxygenase-2 (COX-2)/prostaglandin E2 pathway in hypoxic cancer cells in vitro [89]. In breast and lung cancer spheroids, TRPA1 activates Ca²⁺-dependent antiapoptotic pathways by promoting ROS resistance [90]. Specifically, TRPA1 upregulated by nuclear factor erythroid 2-related factor 2 (NRF2), a transcription factor that, by encoding proteins with antioxidant and anti-inflammatory functions, promotes an adaptive process involving non-canonical oxidative stress defense and canonical ROS defense mechanisms [90]. Furthermore, TRPA1 inhibition attenuates xenograft tumor growth and increases chemosensitivity [90].

The TRPA1 protein has been identified in benign human skin lesions (dermal melanocytic nevi and dysplastic nevi), in cutaneous thin (pT1) and thick (pT4) melanomas, and in two different melanoma cell lines (SK-MEL-28 and WM266-4) [87]. In samples of skin lesion and melanoma, the presence of TRPA1 has been correlated with a progressive increase in oxidative stress and melanocytic transformation, as well as tumor severity. In vitro experiments on melanoma cell lines have shown that TRPA1 activation is associated with the release of H₂O₂, an observation in line with previous findings that have indicated the channel as an oxidative stress sensor and amplifier, a function that might affect tumor cells and proliferation [87].

Recent studies have underlined the role of TRPA1 in cancer pain. In a mouse model of cancer induced by the subcutaneous inoculation of melanoma B16-F10 cells, neuronal TRPA1 has been proposed to mediate mechanical and cold hypersensitivity and thigmotaxis behavior [91]. However, in mouse models of neuropathic pain induced by sciatic partial nerve ligation or ischemia and reperfusion, a prominent role of TRPA1 expressed in Schwann cells has been proposed [84,92]. Hematogenic macrophages recruited by increases in C-C Motif Chemokine Ligand 2 (CCL2) at sites of nerve injury generated a first burst of oxidative stress that, targeting the peripheral glial cell TRPA1, initiated a feed-forward mechanism that, via a Ca²⁺-dependent NADPH oxidase-1 (NOX1), amplified the oxidative stress to sustain pain signals [84,92]. Schwann cell TRPA1 has been similarly implicated in cancer-related pain by regulating, via a macrophage colony-stimulating factor (M-CSF), macrophage expansion and oxidative stress amplification, finally targeting neuronal TRPA1 to signal pain. In this mouse cancer model evoked by the inoculation of melanoma cells in the mouse paw, neuroinflammation and mechanical/cold hypersensitivity are maintained by a feed-forward mechanism, which requires continuous interaction between Schwann cell TRPA1 and expanded endoneurial macrophages throughout the entire sciatic nerve trunk [93].

Pain is also a recurrent symptom of cancer that becomes more frequent and debilitating in the presence of bone metastases, which are a common consequence of many primary tumors, including breast cancer [94]. A prominent role for the TRPA1 channel has also been reported in the development of mechanical hypersensitivity in a mouse model of metastatic bone cancer pain induced by the intramammary inoculation of breast carcinoma cells [95,96]. More recently, TRPA1 has been shown to be a regulator of metastatic bone cancer pain via insulin-like growth factor 1 receptor (IGF-1R) signaling in Schwann cells [97]. IGF-1, derived from osteoclast activation in osteolytic lesions caused by metastatic growth, targets its receptor expressed in Schwann cells, thus promoting an endothelial nitric oxide synthase-mediated TRPA1 activation and ROS release that, via M-CSF-mediated endoneurial macrophage expansion, sustains proalgesic responses.

There are seven known members of the TRPC family, from TRPC1 to TRPC7. TRPC channels are widely expressed in many tissues and cells, including neurons, muscle cells, and epithelial cells. TRPC channels are involved in various physiological processes, such as sensory perception, smooth muscle contraction, hormone secretion, and cell migration [28]. TRPC channels can be activated by various signals, including G-protein-coupled receptors (GPCRs), receptor tyrosine kinases, and intracellular second messengers, such as diacylglycerol (DAG) and inositol trisphosphate (IP₃) [98,99]. Upon activation, TRPC channels allow for the influx of Ca²⁺ ions into the cytoplasm, leading to an increase in the intracellular Ca²⁺ concentration. This Ca²⁺ influx triggers downstream signaling pathways and modulates the activity of various enzymes and transcription factors, ultimately influencing cell function. Aberrant TRPC channel activity has been associated with several diseases and pathological conditions, including cardiovascular disorders, neurodegenerative diseases, and cancer. Therefore, TRPC channels have emerged as potential therapeutic targets, and efforts are underway to develop drugs that modulate their activity for the treatment of these conditions.

TRPC1 is expressed in various types of cancer, including breast, pancreatic, lung, and glioblastoma multiforme. Its dysregulation has been proposed as a prognostic marker for some types of cancer [100], including breast cancer, as its expression is modulated by tumor development and metastasis [101,102,103]. An increased expression of TRPC1 is has been positively correlated with epithelial–mesenchymal transition (EMT), a complex process that induces tumor cells to spread and fight apoptosis, thus conferring a more aggressive phenotype [104,105]. Recently, it has been reported that TRPC1 overexpression increases markers for an EMT-like phenotype, such as zinc finger proteins, SNAI1 (SNAIL) and SNAI2 (SLUG), and VIMENTIN, by increasing invasiveness in mouse breast cancer cell lines in vitro [106]. TRPC1 is also expressed in human lung carcinoma, and high protein levels have been correlated with cancer differentiation and proliferation [107].

Aberrant Ca²⁺ signaling has been implicated in glioma pathogenesis and cell biology influencing cell proliferation, migration, invasion, and angiogenesis [108]. TRPC1 channels, acting as Ca²⁺-permeable channels, have been shown to regulate Ca²⁺ influx in glioma cells [109]. Increased Ca²⁺ influx through TRPC1 channels activates downstream signaling pathways, leading to cell proliferation and survival [109]. A loss of function of TRPC1, mediated by pharmacological or genetic inhibition, was found to reduce the proliferation of multinucleated glioma cells, mainly due to the suppression of store-operated Ca²⁺ entry (SOCE) [109].

TRPC1 channels have been found to promote glioma cell migration through their association with focal adhesion proteins and cytoskeletal rearrangement. Furthermore, TRPC1-mediated Ca²⁺ signaling can activate proteases and matrix metalloproteinases, facilitating the breakdown of the extracellular matrix and promoting glioma cell invasion [110]. TRPC1 channels have been shown to promote the release of pro-angiogenic factors, such as vascular endothelial growth factor (VEGF), from glioma cells, thus inducing endothelial cell proliferation and migration and leading to the formation of new blood vessels within the tumor microenvironment [111].

The TRPC3 protein might contribute to the development of tumor senescent phenotypes. Its downregulation in stromal cells promotes cellular senescence, sustaining inflammation and tumor growth in vivo [112]. TRPC3-mediated Ca²⁺ influx has been suggested as an endothelial cell attraction factor in prostate cancer, thus promoting angiogenesis [88,113]. TRPC3 overexpression has been detected in triple-negative breast cancer cells, and its activation induces an RAS P21 protein activator 4-mitogen-activated protein kinase (RASA4-MAPK) signaling cascade that plays a crucial functional role in preserving proliferation and resistance to apoptosis. A TRPC3 blocker attenuates proliferation, induces apoptosis, and sensitizes cell death to chemotherapeutic agents [114]. The TRPC3 channel is also highly expressed in gastric cancer specimens, and its expression is correlated with malignant progression by modulating the calcineurin B-like 2/glycogen synthase kinase-3 beta/nuclear factor of the activated T cells 2(CNB2/GSK3β/NFATc2) signaling pathway and controlling cell cycle, apoptosis, and intracellular ROS generation [115].

An aberrant Wnt/β-catenin signaling cascade facilitates cell renewal, proliferation, and differentiation in several cancer types [116]. The activation of this intracellular pathway increases the production of the ATP-biding cassette, subfamily B, member 1 (ABCB1), a multidrug efflux transporter that attenuates the effect of cytotoxic drugs in cancer cells. TRPC5 was found to be overexpressed together with ABCB1 in colorectal cancer cells resistant to 5-fluorouracil (5-Fu). TRPC5 silencing inhibits Wnt/β-catenin signaling, thus reducing ABCB1 and consequently reverting resistance to 5-Fu [117]. In a similar manner, TRPC5 channel expression is increased in breast cancer cell lines together with P-glycoprotein (P-gp), another pump overexpressed by cancer cells to remove cytotoxic drugs. TRPC5 suppression reduces P-gp levels and causes a reversal of drug resistance in cells [118]. The mechanism by which TRPC5 regulates P-gp seems to be specifically controlled through the activation of the nuclear factor of activated T cells isoform c3 (NFATc3) [119]. In addition, in breast cancer cells, TRPC5 activation promotes autophagy and chemoresistance via the Ca²⁺/calmodulin-dependent protein kinase beta/adenosine monophosphate-activated protein kinase alpha/mechanistic target of rapamycin (CaMKKβ/AMPKα/mTOR) pathway [120]. It has also been shown that TRPC5 is highly expressed in human breast cancer after long-term chemotherapy treatment, and its presence has been correlated with an increase in the transcription of vascular endothelial growth factor, which, in turn, stimulates tumor angiogenesis [121]. The TRPC5 channel seems to promote metastasis in colon cancer. Colon cancer patients with a high expression of TRPC5 display poorer overall and metastasis-free survival [122]. TRPC5 overexpression, by increasing intracellular Ca²⁺ concentration and mesenchymal biomarker expression, promotes cell migration, invasion, and proliferation [122].

Growing evidence has reported that the pattern of the expression of TRPC6 proteins is upregulated in several pathophysiological conditions, including cancer. TRPC6 has been found to be overexpressed in breast cancer biopsy tissues compared to normal breast tissues [123]. Human breast cancer cells in vitro also display significant levels of TRPC6 expression, and its silencing results in a significant reduction in cell growth [123]. In human hepatocellular carcinoma cells, transforming growth factor beta (TGFβ) is a mediator of motility, invasion, and metastases via the stimulation of Na⁺/Ca²⁺ exchanger 1 (NCX1), and TRPC6 activation regulates TGFβ, thus inducing the formation of a TRPC6/NCX1 molecular complex [124]. The expressions of both TRPC6 and NCX1 are markedly increased in human hepatocellular carcinoma tissues, and their expression levels positively correlate with migration, invasion, and intrahepatic metastasis [124]. An increased TRPC6 channel in cervical cancer cell lines induces cell proliferation, suggesting that channel inhibition might reduce the malignant behavior of the cancer. TRPC6 might be a new target for the prevention and treatment of cervical cancer [125].

TRPM channels are a family of ion channels that regulate sensory perception, cellular homeostasis, and signal transduction. TRPM channels respond to a broad array of stimuli, including temperature, touch, pain, osmolarity, and chemical signals. They are expressed in various tissues and cell types throughout the body, highlighting their importance in numerous physiological functions. TRPM channels have gained significant attention in the field of cancer research due to their potential involvement in tumor progression and metastasis. Several members of the TRPM channel family have been implicated in cancer development and are investigated as potential therapeutic targets [126,127].

TRPM1 gene expression has been identified in benign nevi, dysplastic nevi, and cutaneous melanomas, with a negative association between its presence and melanoma aggressiveness [128,129]. In contrast, TRPM1 protein expression is associated with tumor progression and survival in acral melanoma, supposedly because of the activation of Ca²⁺/calmodulin-dependent protein kinase II (CaMKII), which facilitates the binding of CaMKII with protein kinase B (AKT) and activates AKT, promoting melanoma cell colony formation, mobility, and an increase in tumor growth [130].

TRPM2 is highly expressed in many human cancers (neuroblastoma, breast, gastric, lung, pancreatic, prostate cancer, squamous cell carcinoma, and T-cell leukemia), where its activation increases malignant cell survival [131]. The modulation of TRPM2 via oxidative stress in several pathological conditions has been reported [132]. One additional product derived from oxidative stress, ADP-ribose (ADPR), binds to the C- and N-termini of TRPM2, an action that results in channel activation [133,134,135].

Channel activation also modulates oxidative stress production. TRPM2 opening modulates the hypoxia-inducible transcription factor 1/2α (HIF-1/2α) signaling cascade, including proteins involved in oxidant stress, glycolysis, and mitochondrial function in neuroblastoma xenograft models [136]. TRPM2 inhibition or depletion reduces cell and mitochondria Ca²⁺ influx and decreases activity, autophagy, antioxidant response, and mitochondrial function, thus impairing tumor cell survival [136,137,138,139,140,141]. TRPM2 also has immunomodulatory functions and can influence the tumor microenvironment. TRPM2 activation in immune cells, such as macrophages and dendritic cells, affects their polarization and cytokine production, leading to a modulation of the anti-tumor immune response [142]. Additionally, TRPM2-mediated Ca²⁺ influx influences the release of inflammatory mediators that promote tumor growth and angiogenesis.

TRPM3 plays pleiotropic roles in cellular Ca²⁺ signaling and homeostasis [143]. TRPM3 has been identified in several cancer types in mammals, including kidney cell carcinoma, glioma, melanoma, and melanoma-associated retinopathy (MAR) [144,145,146]. The TRPM3 channel supports the growth of clear cell renal cell carcinoma by promoting autophagy [144]. An increased expression of TRPM3 in renal cell carcinoma leads to Ca²⁺ influx, which elicits the activation of CaMKII, 5′-AMP-activated protein kinase (AMPK), and Unc-51-like autophagy-activating kinase 1 (ULK1), as well as the formation of phagophore [147].

MiR-204 is an intron micro-RNA (miRNA) located between exons 7 and 8 of the TRPM3 gene. A reduction in miR-204 induced by the higher methylation of host gene TRPM3 in gliomas can promote cell migration and enhance cell stemness [148]. It has been shown that TRPM3 interacts with the signal transducer and activator of transcription 3 (STAT3) via the activation of STAT3-suppressing miR-204 expression. Furthermore, the downregulation of miR-204 via the methylation of the promoter of its host gene TRPM3 leads to the activation of the Src-STAT3-NFAT pathway, promoting glioma stem cell invasion and stem cell-like phenotype [149].

In physiological conditions, TRPM4 controls cell migration [150]. It regulates the activation of T lymphocyte and mast cells, together with the migration of dendritic and mast cells [151,152]. Under inflammatory conditions, TRPM4 is involved in vascular endothelial cell migration and ROS production [153]. TRPM4-mediated effects on cell migration are at least partially due to the activation of Rac family small GTPase 1 (Rac1-GTPase), a key regulator of cytoskeletal dynamics and cell polarity [154].

TRPM4 channel expression has been described in several cancers, including prostate [155,156,157], urinary bladder [158], cervical [159], colorectal [160,161], liver [162], and large B cell lymphoma [163]. In cancer cells, TRPM4 upregulation is associated with cancer cell migration, proliferation, and invasion. A recent study has shown that TRPM4 upregulation and its conductivity control the viability and cell cycle of colorectal cancer cells [164]. Another study revealed that TRPM4 gene defects mechanically engaged intestinal barrier integrity by depressing the generation of ROS and decreasing mucus production, thus promoting chronic bowel inflammation, a risk factor for colorectal cancer [160]. A more recent study indicated that an attenuated expression of TRPM4 is associated with the development of endometrial carcinoma and breast cancer through the hyperactivation of the phosphoinositide 3-kinase/protein kinase B/mammalian target of rapamycin (PI3K/AKT/mTOR) pathway, which regulates cell transcription, translation, migration, metabolism, proliferation, and survival [165]. In addition, within normal lymphoid tissues, including the tonsils, lymph nodes, and appendix, human normal B cells express low levels of TRPM4, while in diffuse large B cell lymphoma, a higher TRPM4 protein level has been detected, which confers significantly poorer patient outcomes [163]. Similarly, a higher level of TRPM4 protein correlates with a higher risk of recurrence following radical prostatectomy [157].

TRPM6 is mostly expressed in the kidneys, distal small intestine, and colon [166]. The TRPM6 channel is permeable to magnesium (Mg²⁺), thus assuming a relevant role in epithelial Mg²⁺ transport and active Mg²⁺ absorption, especially in the gut and kidneys [167]. Hypomagnesemia is evidenced in cancer patients after cisplatin-based chemotherapies [168], and it has emerged as the most notable adverse effect of the anti-epidermal growth factor receptor (EGFR) monoclonal antibody, cetuximab, which is used widely for the treatment of advanced colorectal cancer cells [169]. The downregulation of the TRPM6 channel is present in 80% of primary tumors in colorectal cancer cells, whereas its high expression increases patient survival [170].

TRPM8, also defined as a “cold receptor”, as it is activated by chemical cooling agents (such as menthol) [171], exhibits an increased expression in several cancer subtypes, including colon, breast, and prostate tumors, and it is considered to be a useful prognostic marker [172,173,174]. TRPM8 channels in cancer prognosis are associated with the modulation of cell viability, proliferation, migration, and apoptosis. For example, TRPM8 activation may regulate AMPK activity by modifying cellular autophagy to control the proliferation and migration of breast cancer cells. TRPM8 knockdown decreases basal autophagy, while TRPM8 overexpression increases basal autophagy in several mammalian cancer cell types. The activation of autophagy-associated signaling pathways for AMPK and unc-51-like kinase 1 (ULK1), as well as the production of phagophores, are part of the TRPM8 strategy for controlling autophagy [175].

TRPM8 involvement in the death and apoptosis of bladder cancer cells is due to the modulation of mitochondrial activity [176,177]. It has also been reported that, in glioblastoma, TRPM8 channels modulate the expression of apoptosis-related factors through the p38/MAPK pathway [178,179]. In colon, oral, esophageal, bladder, and breast cancers, TRPM8 seems directly involved in invasiveness and metastasis via the regulation of the epithelial–mesenchymal transition process (EMT) [173,180,181,182].