According to the latest Global Cancer Statistics Report (1), there were nearly 20 million new cancer cases (including non-melanoma skin cancer) and 9.7 million deaths from cancer (including non-melanoma skin cancer) in 2022, cancer has become a public health problem that seriously jeopardizes the health of human beings. Most patients diagnosed with cancer are in the middle and late stage. However, among the treatment methods, surgical complications, radiotherapy and chemotherapy toxic side effects are large, which seriously affects the quality of life of patients. At present, the treatment of cancer is transitioning from traditional surgery, chemotherapy and radiotherapy to new immunotherapy, targeted therapy and ion channel therapy. Finding new targets or low-toxicity and high-efficiency drugs for cancer treatment has always been a hot field of medical research. TRPV1 has emerged as a potential target for cancer treatment due to its role in regulating tumor growth, cell apoptosis, and the tumor micro-environment.

Capsaicin receptor - transient receptor potential vanillate receptor (TRPV1) is a non-selective cation channel that can be activated by temperature, physical and chemical stimuli (2). Its activation regulates a variety of biological responses, such as apoptosis and proliferation (3), metabolism and glucose homeostasis control (4), as well as nociception and body temperature. Recent studies have shown that TRPV1 receptor plays an important role in tumor biology through a variety of pathways. However, their specific mechanisms and roles in different types of cancer are still not fully understood, and TRPV1 modulators still have a long way to go before becoming anti-tumor drugs due to their side effects. We believe that TRPV1 is a heat-activated channel that can be activated by some odorous traditional herbs. TRPV1 receptor is a popular target for cancer therapy, and these odorous traditional herbs may also be potential drugs for cancer prevention and treatment.

This review aims to summarize the mechanisms by which TRPV1 receptors influence cancer progression, including their role in tumor cell proliferation, apoptosis, invasion, and tumor micro-environment. In addition, the anti-tumor potential of odorous traditional herbs that regulate TRPV1 is also discussed, hoping to develop anti-tumor drugs targeting TRPV1 receptors in the future.

Transient receptor potential vanilloid receptor was the first member of the transient receptor potential cation channel family to be discovered, it was cloned from the rat dorsal root ganglion by Caterina et al. in 1997 (5), and later formally named TRPV1 (6). TRPV1 is a multi-modal injury receptor that can be activated or variably modulated by temperature, physical, and chemical stimuli (7). In addition to capsaicin, its thermal sensitivity is activated by other endogenous substances (ATP, bradykinin, nerve growth factor, inflammatory mediators such as arachidonic acid amide and prostaglandins) and exogenous physical or chemical stimuli (camphor, resinaceous toxins, vanilloid toxins 1-3, ginger, and ethanol) (8). Upon activation of the post-cation channel TRPV1, extracellular Ca²⁺ flows into cells and releases intracellular cisterna Ca²⁺, resulting in increased intracellular Ca²⁺ concentration and mediating various basic cellular activities, such as muscle cell contraction, neuronal activity and transmitter release, cell proliferation and apoptosis (9).

TRPV1 transmembrane protein is a homologous tetramer composed of four identical subunits assembled around a central water pore, each consisting of six transmembrane domains (S1-S6), a long N-terminal region, and a short C-terminal region (10, 11). There is a short hydrophobic hole between S5 and S6 that mediates the passage of ions; The N-terminal region contains several phosphorylation sites and six ankyloprotein repeats that bind calmodulin and ATP; The C-terminal region contains the TRP region, multiple calmodulin binding regions, and endogenous substance binding sites, which can bind protein kinase C (PKC), Ca²⁺/calmodulin-dependent protein kinase II (CaMKII), and phosphatidylinositol-4,5 diphosphate (PIP2) (12). Compound binding to these sites modulates TRPV1 sensitivity and function, we need to elucidate their ligand structures and corresponding TRPV1 sites, mechanisms of action in the cancer process, and final effects. (The structure of TRPV1 is shown in Figure 1 ).

TRPV1 mRNA and protein are expressed in many cancer cell lines, and the expression levels in different cancer tissues are significantly different from those in their normal tissues, suggesting that it is involved in key processes of cancer progression. Weber LV et al. found that the expression of TRPV1 in breast cancer tissues and cells was significantly higher than that of healthy breast tissues, and that the average expression level was the highest in the triple-negative breast cancer subtypes (13). TRPV1 expression in cervical cancer tissues was higher than that in precancerous epithelial tissues and normal epithelial tissues, and its up-regulated expression was significantly correlated with more advanced tumor stage and poorer tumor grading. Over-expression of TRPV1 significantly increased the proliferation and clonogenic ability of cervical cancer cells (14).

However, the expression level of TRPV1 in some cancer tissues was lower than that in their normal tissues. It was found that the expression of TRPV1 in melanoma tissues and cell lines was significantly lower than that in nevus tissues and normal melanocytes (15). The expression of TRPV1 was lower in cervical squamous cell carcinoma (CSCC) and cervical adenocarcinoma than in normal group, and lower in CSCC than in cervical adenocarcinoma group (16).

Apparently the expression level of TRPV1 in each cancer cell line is highly heterogeneous, and the expression of TRPV1 is associated with different tumor micro-environments and different cancer-associated pathways. The expression level of TRPV1 also changed in the same cancer tissue, which was related to the grade of cancer tissue, pathological stage and tumor stage. Therefore, the expression level of TRPV1 can be used for the diagnosis and prognosis of cancer. The changes in TRPV1 expression, the mechanism of change and its role depend on different cancer cell types, which still need further study. (Compared with normal tissues, the changes and significance of TRPV1 expression level in cancer tissues are shown in Table 1 ).

TRPV1 receptor is a popular target for the development of anti-cancer drugs. Pharmacological modulators of specific TRPV1 channels may promote or induce cancer cell death, and may also be effective in reducing cancer cell proliferation, invasion, and metastasis. In addition, it can achieve anti-cancer effects by regulating the tumor micro-environment. TRPV1 modulators can enhance the effect of chemoradiotherapy, and the synergistic use of TRPV1 modulator can reduce the required dose of chemoradiotherapy to control cancer and reduce the toxic side effects of chemoradiotherapy. TRPV1 agonist combined with chemoradiotherapy is a feasible strategy for cancer treatment (58). However, the systemic use of TRPV1 modulators causes side effects such as hyperthermia, burns and respiratory injury (59), which severely limits its application. Only low-concentration cream or transdermal patch types of topical analgesic preparations are currently in clinical use (60). The key point is how to ensure the anti-cancer effect of TRPV1 modulators while overcoming their side effects. Some studies have combined TRPV1 modulators with the latest drug delivery systems in the hope that precise localized drug delivery can avoid the activation of systemic TRPV1 receptors (61, 62); Others have been devoted to the development of new structural variants of TRPV1 modulators (63). However, all the current studies are still in the experimental stage, and there is still a long way to go before practical clinical application.

We may be able to turn our attention to the potential of traditional herbs, which traditional Chinese medicine categorizes as odorous traditional herbs that elicit odorous flavors and heat sensations, and use them to treat tumors (64, 65). TRPV1 receptors are activated by a number of irritating substances and temperatures above 43°C. Studies have shown that many odorous traditional herbs activate the TRPV1 receptor. The efficacy of odorous traditional herbs is highly similar to the physiological functions mediated by TRPV1 receptors, such as dispelling cold and relieving pain (66). Capsaicin, an extract of odorous traditional herbs, activates the TRPV1 receptor against tumors (67). Gingerol, an extract of ginger (68), has anti-tumor effects, studies have shown that gingerol can activate TRPV1 (69), but no one has studied whether it is anti-tumor through the TRPV1 receptor pathway. Curcumin, an extract of turmeric, also has anti-tumor effects (70), studies have shown that curcumin can antagonize TRPV1 receptors (71). The TRPV1 receptor is a popular target for treating cancer, We hypothesize that these odorous herbs can modulate the TRPV1 receptor to exert anti-tumor effects, which needs further research and may be a more promising direction for finding anti-cancer drugs that target TRPV1 receptors. We summarize the currently known herbs that regulate TRPV1 receptors, as shown in Table 2 :

TRPV1 is a multifunctional cell receptor that is widely distributed in human tissues and can sense various stimuli and be converted into calcium-based cascades, a variety of physiological and pathological processes based on it are being discovered. TRPV1 receptors are involved in the development of cancer in various ways, and the specific mechanisms have not been fully elucidated. The occurrence of tumor is a multi-factor, multi-step, complex and long biological process. In the process of development, the uneven distribution and effects of environmental factors and the randomness of gene mutations lead to high heterogeneity of tumors. TRPV1 receptor is also affected by these factors in the occurrence and development of various types of cancer, activating different factors and molecular pathways to produce different effects. Therefore, activation of TRPV1 has different effects on different types of cancers, which needs to be further investigated.

The TRPV1 receptor is a biomarker for predicting and diagnosing cancer, Its expression levels in cancer tissues are highly heterogeneous. It is necessary to study its progression in specific cancer types, determine the range of its expression levels and the relationship between its changes and prognosis. A recent study (24) revealed for the first time the expression, clinical value and potential mechanism of TRPV1 in pancarcinoma, which is also a direction.

In terms of the regulation of the apoptosis-proliferative balance of cancer cells and the tumor micro-environment, we need to consider that TRPV1 receptor is involved in the cancer process in multiple ways, the results of the studies may be different, which is the reason why many studies have conflicting results. When designing relevant experiments, we should carefully consider the type of cancer cell, the type of experiment (in vivo or in vitro), the dose, concentration and duration of action of TRPV1 modulator, etc. We also need to circumvent the effects of the non-TRPV1 pathway of TRPV1 modulators on cancer and the effects of other TRPV1 cancer pathways so that the experimental results can be accurate. At present, the research on the role of TRPV1 in cancer is still in the initial stage. How to control multiple confounding factors in the experiment to make the results accurate is the current problem. In addition, it needs to overcome its serious side effects in humans.

There is no doubt that manipulating the TRPV1 receptor could treat cancer, and the possibilities are endless. We think it is very promising to find suitable medicines from traditional herbs, because traditional herbs have been practiced for thousands of years and have a safe dose range, they can activate TRPV1 receptors while avoiding side effects. We summarized the currently known odorous herbs that can regulate TRPV1 receptors, hoping to develop anti-cancer drugs targeting TRPV1 receptors in the future.