Advances in the treatment of malignant tumors with neurological drugs

Abstract

The nervous system governs the body’s components and is essential for the physiological functions of all organ systems. The nervous system governs how the body senses, processes, and responds to its environment. Through a complex network of neurons and supporting cells, it connects sensory organs with the brain and spinal cord, and coordinates communication with target organs and tissues throughout the body. This integration of sensory, motor, autonomic, and endocrine functions makes the nervous system essential for maintaining homeostasis and systemic coordination.Consequently, it is anticipated that the nervous system exerts parallel regulatory influences on cancer. Over the past decade, studies have demonstrated a reciprocal relationship between the nervous system and cancer. Taking gliomas, prostate cancer, and breast cancer as examples, where specific nerve types (parasympathetic, sympathetic, or sensory) directly or indirectly control the initiation, progression, and metastasis of cancer. Similarly, cancer can reshape and hijack the structure and function of the nervous system. Chemotherapy has traditionally been the primary and most effective antitumor treatment, while the discovery of neuro-tumor interactions unveils novel strategies for repurposing neuroactive agents as adjuncts to this conventional therapeutic approach. This review elucidates cancer neuroscience through the examples of gliomas, prostate cancer, and breast cancer. Structured around key neuropharmacological receptors, the review systematically explores the potential applications of neuroactive agents and their targets across a broad spectrum of cancer therapies.

Introduction

Before the 1960s, all drugs used for cancer treatment were purely organic compounds. Despite the growing incidence of various cancers globally, chemotherapy remains the most common and effective treatment method for cancer patients.

As research into cancer mechanisms deepens, an exciting frontier has emerged: the intersection between the nervous system and cancer. The central and peripheral nervous systems regulate both physiological and pathophysiological processes in the body. Consequently, the hypothesis that the nervous system regulates cancer has been proposed. Given that cancer initiation, growth, and progression are closely associated with the tumor microenvironment, the nervous system plays a pivotal role in promoting cancer mechanisms, from tumorigenesis to progression and metastasis. Conversely, cancer and its treatments can impact and reshape the nervous system, creating pathological feedback loops that not only cause neurological dysfunction but also drive tumor malignancy.

Growing experimental evidence supports this connection, with studies addressing various aspects such as the regulation of tumor phenotypes by the nervous system, the systemic effects of tumors on nervous system function, and local remodeling of tissue innervation [1]. Clinically, perineural invasion is a potential indicator for adjuvant radiotherapy in several malignancies, including prostate, breast, pancreatic, esophageal, and thyroid cancers [2]. Beyond irradiating nerve-invaded tumors, molecular targeting of the tumor-nerve axis holds significant potential in clinical oncology [2]. The emerging discipline of “cancer neuroscience” examines the interplay between fundamental components of the nervous system (neurons, glial cells, and peripheral nerves) and cancer cells, forming an integrated system that impacts tumor initiation, progression, metastasis, and the tumor microenvironment [3]. This field promises to be a cornerstone for discovering new cancer treatment targets.

The growing evidence for neural influences in cancer advocates for an integrated systems-level approach to tumor biology in which neural signaling can play a critical regulatory role in tumor initiation, progression, and treatment response. This review by integrating neuropharmacological perspectives, the review emphasizes the exploration of neuroactive agents and their targets across a broad spectrum of cancer treatments, offering innovative insights for repurposing neuropharmacological drugs in oncology. Furthermore, selects gliomas, prostate cancer, and breast cancer as representative malignancies of the central nervous system (CNS) and peripheral nervous system (PNS), respectively. It synthesizes the latest discoveries in cancer neuroscience to underscore the pivotal role of neuro-tumor interactions in cancer therapy.

Gliomas

When discussing the relationship between nerves and tumors, the interactions between neurons and brain tumors warrant significant attention. Gliomas, the prevalent primary brain tumors in children and adults, consist of various tumor cell types such as oligodendrocytes and astrocytes. Although these tumors were initially named “astrocytomas” due to their histological resemblance to astrocytes, it is now understood that most gliomas originate from stem cells and progenitor cells of the oligodendrocyte lineage [4]. Neuronal activity significantly influences the proliferation of oligodendrocyte progenitors, suggesting that imbalances or “hijacking” of myelin plasticity may drive the malignant proliferation of this devastating primary brain tumor [5].

Neuronal activity not only fosters glioma growth but also regulates glioma initiation and maintenance. For instance, stimulating optic nerve retinal ganglion activity can enhance low-grade glioma growth [5]. Conversely, suppressing olfactory neuronal activity or reducing olfactory experiences can slow tumor growth [4]. In an optic pathway glioma model, tumors fail to form in the absence of visual experience, even in the presence of genetic susceptibility, in stark contrast to control animals raised with normal visual experiences [5]. After tumor formation, reduced visual experiences also hinder the maintenance of the optic nerve pathway.

Neuronal activity promotes the development of gliomas, while glioma cells, in turn, further increase neuronal activity by enhancing neuronal excitability [6, 7]. The link between gliomas and seizures is well-established. Breakthrough research by the Sontheimer group revealed how gliomas directly elevate neuronal excitability [7]. This process involves multiple mechanisms, including glutamate release by glioblastoma cells through the glutamate-cysteine exchange system Xc − in nonsynaptic regions [6]. In the tumor microenvironment, the loss of inhibitory neurons, altered neuronal responses to GABA, and synaptogenic factors secreted by gliomas, such as galectin-3 and thrombospondin-1 (TSP-1), play significant roles [8]. Synaptogenic factors, typically secreted by astrocytes, are critical for astrocyte function.

Glioma-induced cortical hyperexcitability was initially observed in mice and has since been confirmed in awake, resting adult glioblastoma patients via intraoperative electrocorticography, as well as during cognitive tasks [5]. As a measure of oscillatory brain activity, ,measurements of broadband power using magnetoencephalography (MEG) in adult glioma patients reveal that both overall and peritumoral broadband power negatively correlate with progression-free survival [6]. Pathological neuronal hyperactivation linked to gliomas may drive epileptogenesis while simultaneously potentiating pro-tumorigenic processes through activity-dependent mechanisms.

Synaptogenic factors secreted by gliomas can also promote functional remodeling of neural circuits. Glioma cells secrete the synaptogenic factor TSP-1, which facilitates normal circuit remodeling and enhances glioma cell responsiveness to neurons, a crucial mechanism [8]. The secretion of synaptogenic factors affects synaptic connectivity between neurons and also between neurons and gliomas.Glioblastoma patients with highly connected gliomas exhibit significantly shorter overall survival [8]. Mechanistically, neuronal activity and glioma progression exhibit a bidirectional interplay: neuronal activity accelerates glioma microtubule reorganization and invasion via paracrine growth factors (e.g., BDNF, NLGN3), electrochemical synaptic communication, and potassium/calcium ion signaling, while glioma cells remodel neural circuits by releasing glutamate and other neuroactive substances, fostering a tumor-promoting microenvironment (Fig. 1).The elucidation of neuro-glioma reciprocal interactions has significantly advanced our understanding of glioma pathophysiology while unveiling potential therapeutic avenues targeting these neural-tumoral regulatory mechanisms.

Fig. 1.

The interplay between neurons and gliomas within the central nervous system. Neuronal activity influences glioma growth, occurrence, and maintenance. Glioma cells release glutamate and synaptophysin, which enhance neuronal excitability and remodel neural circuits, thereby increasing neuronal activity in the tumor microenvironment. Neuronal activity enhances glioma progression by accelerating tumor microtubule reorganization and invasion rates. This is achieved through the regulation of paracrine growth factor secretion (such as BDNF and NLGN3), synaptic electrochemical communication between neurons and glioma cells, and the influence of potassium-induced depolarizing currents and calcium transient waves

Prostate cancer

The prostate is a highly innervated organ, and its normal growth, balance, and function are regulated by the parasympathetic and sympathetic nervous systems. Initial surgical studies on denervation suggested that prostate atrophy is associated with nerve supply loss [9]. On the other hand, adrenergic agonists have been shown to cause prostate hyperplasia [9]. Furthermore, histopathological analysis of prostate cancer has revealed a phenomenon known as perineural invasion, where tumor cells invade and grow along nerves [10]. Retrospective analyses of clinical and pathological characteristics in prostate cancer patients indicate that perineural invasion and increased nerve diameter are markers of poor prognosis [10].

Co-culture systems of dorsal root ganglia and human prostate cancer cells have shown that neurons can promote the proliferation of prostate cancer cells, providing preliminary evidence that neurons facilitate cancer cell growth [11]. Further research has demonstrated that the growth and progression of prostate cancer are related to other cellular and molecular components of the nervous system. In both xenograft and Myc-driven genetically modified prostate cancer mouse models, β2-adrenergic signaling enhances angiogenesis by reducing oxidative phosphorylation through β2-adrenergic receptor expression on endothelial cells within the tumor stroma [12].

Breast cancer

The nervous system is essential in breast development and carcinogenesis. Similar to the interaction between the central nervous system and gliomas, a bidirectional interplay also exists between the peripheral nervous system and breast cancer (Fig. 2). Some studies have revealed significant adrenergic sympathetic nerve distribution in the breast. Brain-derived neurotrophic factor (BDNF) produced by the breast and its signaling through its receptor TrkB on sensory neurons is essential for the formation of sensory nerve supply in female breasts [13]. In males, androgen action blocks the BDNF-TrkB signaling pathway in sensory neurons, confirming the neurobiological mechanisms of sexual dimorphism in organ development [14].

Fig. 2.

The regulation of breast cancer by the peripheral nervous system. The sympathetic nervous system innervates breast tumors. Breast cancer cells produce increased amounts of nerve growth factor, leading to enhanced neurite growth in related nerves. Local sympathetic nerve fibers enhance primary breast tumor growth and metastasis by releasing norepinephrine, which upregulates immune checkpoint molecules like PD-1 and PD-L1 and increases tumor-infiltrating regulatory T cells

Studies of breast cancer samples reveal a strong link between perineural invasion and the disease’s progression, metastasis, and clinical staging [15]. When human breast cancer cells were co-cultured with rat neurons, the nerve growth factor (NGF) produced by breast cancer cells increased, promoting the growth of nerve fibers [16]. Further in vivo studies observed sympathetic nerve innervation in human breast tumors and spontaneous breast cancer mouse models [17]. Chemical ablation of these sympathetic fibers reduced tumor burden [17]. Recent research employing retrovirus-based genetic techniques to specifically target local autonomic nerves within tumors has provided a more precise characterization of neural innervation in the breast cancer microenvironment [18]. In an in situ human breast cancer xenograft model, specific activation of local sympathetic nerve fibers through the release of norepinephrine promoted primary breast tumor growth and distant metastasis [19]. High doses of capsaicin can destroy sensory neurons, promoting breast cancer metastasis and inducing more aggressive gene expression phenotypes, like the effect of parasympathetic nerves [19].

The nervous system is crucial in controlling breast cancer metastasis. In systemic injection and in situ breast cancer mouse models, chronic stress induced by inhibitory paradigms significantly increased tumor colonization and metastasis to distant tissues [20].

Neuroreceptors and cancer

Research on the relationship between various cancers and the nervous system highlights its essential role in cancer progression, including neuronal promotion of prostate cancer cell proliferation and the involvement of other nervous system components in the growth and progression of prostate cancer. This leads us to further consider whether other receptors in the nervous system and their regulatory mechanisms are also associated with cancer development. The extensive presence of nicotinic acetylcholine receptors (nAChRs) and their physiological agonist acetylcholine in mammalian cells, coupled with their regulatory role in cancer cells and the tumor microenvironment, offers a novel perspective [21]. This resonates with the mechanisms of the nervous system in cancer, suggesting that the onset and development of cancer may be influenced by various neuro-related factors, necessitating deeper research and understanding from a broader neurobiological perspective. The following will describe the roles of various key receptors in the nervous system in cancer and prospect the application of neuropharmaceuticals in cancer treatment.

Acetylcholine receptors

The extensive presence and varied regulatory roles of nAChRs in mammalian cells indicate that prolonged exposure to tobacco components or other environmental and lifestyle factors could modulate these receptors, potentially facilitating cancer progression [22]. Tobacco-specific carcinogenic nitrosamines, including 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) and N-nitrosonicotine (NNN), act as agonists for α7nAChR and α-βnAChR heteromers, respectively [23]. Upon binding to α7nAChR, NNK induces calcium ion influx into lung cells and activates voltage-gated calcium channels, causing membrane depolarization [23]. Prolonged exposure to NNK increases α7nAChR expression [23]. Both acute and chronic nicotine exposures similarly affect nAChR function, impacting cation channel activity and receptor upregulation [23]. Nicotine or NNK promotes the proliferation of pulmonary neuroendocrine cells (PNECs) or small cell lung cancer (SCLC) cells in vitro by activating protein kinase C (PKC), RAF1, ERK1/2, and transcription factors FOS, JUN, and MYC. Selective α7nAChR antagonists can block these responses, such as alpha-bungarotoxin and alpha-conotoxin MI [23, 24]. Serotonin uptake inhibitors such as fluoxetine and paroxetine can counteract the effects of nicotine or NNK [24]. Calcium channel blockers, such as dihydropyridine drugs, significantly reduce DNA synthesis responses to nicotine or NNK [24]. NNK promotes SCLC cell migration through ERK1-ERK2-dependent phosphorylation of m-calpains and µ-calpains [25]. Inhibition of ERK1-ERK2 or silencing of calpain via small interfering RNA can block this response [25]. NNK prevents SCLC cell apoptosis by activating Bcl-2, a mechanism that can be inhibited by the PKC inhibitor staurosporin, the ERK1-ERK2 inhibitor PD98059, or MYC silencing [26]. These findings indicate that α7nAChR centrally regulates SCLC cell proliferation, apoptosis, and migration by promoting the release of autocrine growth factors like serotonin and bombesin, along with potentially other neuropeptides. In vitro studies show that PKC or ERK1-ERK2 inhibitors, along with agents that elevate intracellular cAMP, markedly decrease nAChR-induced DNA synthesis in SCLC cells [27]. Nicotine also stimulates angiogenesis in endothelial cells via α7nAChR.This observation suggesting its important role in angiogenesis during cancer development [28].

Unlike PNECs and SCLC cells, bronchial and bronchiolar epithelial cells, as well as alveolar type II cells, express both α7nAChR and various heteromeric nAChRs. These lung cancers are collectively known as non-small cell lung cancers (NSCLCs). Research indicates that nicotine and NNK activate the PI3K-Akt pathway and NF-κB, promoting cell proliferation and reducing chemotherapy-induced apoptosis [29]. Agonists of α7nAChR or heteromeric nAChRs containing α3 or α4 subunits have similar effects, suggesting that these three receptors mediate the observed responses. However, in the lungs of smokers, the response to nicotine or NNK is primarily mediated by α7nAChR, as heteromeric nAChRs are desensitized. Studies on PACs from alveolar type II cells indicate that nicotine-induced apoptosis resistance involves Akt signaling through survivin (BIRC5) and XIAP (BIRC4), while α7nAChR activation promotes non-small cell lung cancer proliferation via β-arrestin-SRC.α7nAChR antagonists can inhibit the response to NNK, while the effects of NNN are inhibited by heteromeric nAChR antagonists [30]. Recent research indicates that nicotine prompts immortalized large airway epithelial cells to secrete epidermal growth factor (EGF) [31]. EGF binds to EGFR, activating the Ras-Raf-Erk cascade, which selective α7nAChR antagonists can block [31]. This finding supports the physiological role of nAChR in modulating growth factor release, suggesting that intracellular signaling in NSCLC cells and their normal progenitors is mainly driven by EGF release. Based on this explanation, the downstream signaling events of nAChRs in these cells are characterized by the effects of EGFR downstream.

In vitro studies on colon cancer cells show that nicotine enhances norepinephrine and epinephrine production, promoting cell proliferation, which can be inhibited by α7nAChR antagonists [32].

Downstream signaling of α7nAChR and heteromeric nAChRs containing α3 and α5 subunits has been observed in oral epithelial cells associated with oral cancer and esophageal squamous cells linked to esophageal cancer [33]. NNK exhibits a strong affinity for α7nAChR, whereas NNN shows a high affinity for heteromeric nAChRs, paralleling observations in lung cancer cells [34]. Nitrosamines promote cell proliferation through the Ras-Raf-ERK1/2 and JAK2-STAT3 pathways, which activate NF-κB and induce GATA3 and STAT1 signaling, while suppressing apoptosis.The expression levels of SluRP1 (secreted Ly6-PLAUR-related protein 1) and SlURP2 are decreased.

Nicotine activates the Ca2⁺-dependent ERK1-ERK2 cascade through α7nAChR, promoting mesothelioma cell proliferation and preventing apoptosis by phosphorylating NF-κB and BAD [35]. Nicotine has been reported to activate ERK1-ERK2 and STAT3 pathways downstream of nAChR and β-adrenergic receptors in bladder cancer cells [35]. The results indicate that in these cancers, nAChR-mediated catecholamine synthesis and release concurrently trigger EGF release or EGFR deactivation. Together, these findings suggest that nAChR activation not only stimulates catecholamine release but also modulates EGFR activity, potentially promoting proliferative oncogenic signaling pathways and tumor development.

Adrenergic receptors

The β-adrenergic system comprises catecholamines and their α- and β-adrenergic receptors. Recent research has revealed that certain cancer cells possess the complete set of enzymes necessary for epinephrine synthesis and can secrete it upon stimulation by nicotine and other factors [36]. Epinephrine and norepinephrine bind to adrenergic receptors with different affinities. Recent studies indicate that biological factors, particularly prolonged stress-related stimuli, may accelerate cancer progression primarily through the activation of the β-adrenergic system [37]. A growing body of research has confirmed the presence of the β-adrenergic signaling pathway within tumors(Fig. 3).

Fig. 3.

The β-adrenergic signaling pathway within tumors. Catecholamine binding to β-adrenergic receptors activates adenylyl cyclase via gas, facilitating ATP conversion to cAMP. The transient fluctuations of intracellular cAMP activate two major biochemical effector systems. cAMP activates protein kinase A (PKA), leading to the phosphorylation of target proteins such as CREB/ATF and GATA transcription factors, which subsequently activate PI3K/AKT/MTOR/P70S6K/HIF1 and β-adrenergic receptor kinase (BARK). BARK facilitates β-arrestin recruitment to suppress β-adrenergic receptor signaling and initiates Src kinase activation, subsequently triggering transcription factors like STAT3 and downstream kinases such as focal adhesion kinase (FAK). The activation of FAK can enhance the cell’s resistance to apoptosis, such as resistance to anoikis. Furthermore, PKA-dependent activation of the Bcl-2 family member BAD can confer resistance to chemotherapy-induced apoptosis in cancer cells. Conversely, cAMP activates EPAC in the second major effector pathway, initiating the Rap-1a-mediated B-Raf/mitogen-activated protein kinase signaling cascade, which subsequently influences cellular processes, including AP-1 and NF-κB modulation. β-adrenergic signaling typically triggers transcriptional responses that upregulate genes linked to inflammation, angiogenesis, tissue invasion, and epithelial-mesenchymal transition (EMT), all of which are related to metastasis. This signaling pathway influences cancer biology by directly targeting tumor cells with β receptors and modulating myelopoiesis and tumor recruitment. It activates transcription in monocytes and/or macrophages with β receptors and supports the growth and differentiation of vascular endothelial cells and pericytes. In summary, stress hormones activate various signaling pathways that enhance tumor growth, angiogenesis, and metastasis through numerous tumor-related factors

The β-adrenergic system significantly influences various aspects of cancer initiation and progression, including growth and metastasis. Propranolol, a non-selective adrenergic receptor antagonist, effectively nullifies chronic stress-induced tumor growth [38]. In contrast, terbutaline, a β2-adrenergic receptor agonist, leads to a similar increase in tumor weight [38]. In mouse models, chronic stress exposure leads to stress-related hormones inhibiting anoikis in cancer cells. This effect may promote tumor growth by activating focal adhesion kinase (FAK). Research on prostate and breast cancer cells demonstrated that epinephrine activation via the β2-adrenergic receptor/PKA/BAD pathway inhibits apoptosis, thereby decreasing cancer cell susceptibility to apoptosis [39]. A recent preclinical model study further confirmed that stress hormones such as epinephrine promote prostate cancer progression by inhibiting apoptosis mediated by the epinephrine/β2-adrenergic receptor/PKA/BAD anti-apoptotic signaling pathway [40]. Both epinephrine and norepinephrine can induce colorectal cancer cell proliferation via adrenergic receptors, particularly the β2 receptor [41]. Reports suggest that adrenergic receptor activation produces diverse effects on breast cancer cells. In these studies, adrenergic receptor agonists reduced both in vitro cell proliferation and in vivo tumor growth [42].

While angiogenesis is typically quiescent in most adult tissues, it is abnormally activated in tumors. Compared to normal blood vessels, the vasculature within tumors is markedly immature. Multiple cancer models provide solid evidence that epinephrine and norepinephrine upregulate VEGF expression, promoting tumor angiogenesis and aggressive growth [43]. Adrenergic receptor signaling in response to epinephrine and norepinephrine has been shown to elevate angiogenesis factors, including interleukin-6 (IL-6), IL-8, and matrix metalloproteinases (MMP)-2 and MMP-9, in various cancer cells [44]. These findings suggest the possibility of an amplification cascade between these factors, synergistically enhancing angiogenesis and tumor invasiveness. The adrenergic receptor antagonist propranolol can fully inhibit the secretion and functions of these factors, suggesting that receptor blockers may have therapeutic potential in cancer treatments. Additionally, Norepinephrine enhances MMP-9 and VEGF levels in ovarian cancer cells and promotes MMP-9 secretion from macrophages derived from ovarian cancer samples [45]. Studies suggest that tumor-associated macrophages (TAMs) and their released MMP-9 play important roles in angiogenesis [45]. A recent study by Park et al. also highlights this finding.demonstrated that norepinephrine stimulates VEGF expression in various prostate, breast, and liver cancer cell lines through an HIF-1-dependent mechanism [46]. Subsequent studies revealed that propranolol effectively inhibited VEGF production in tumor cells and decreased norepinephrine-stimulated HIF-1α expression [46].

Tumor metastasis, a multistep cellular and biological process involving the invasion-metastasis cascade, is the primary cause of cancer-related mortality [47]. The β-adrenergic system appears to play a role in each stage of the invasion-metastasis cascade. Extensive evidence indicates that the stress hormones epinephrine and norepinephrine stimulate various cancer cell lines and models linked to metastasis to secrete MMP-2, MMP-7, and MMP-9, facilitating cancer cell invasion and migration by breaking down the extracellular matrix [48]. β-receptor blockers, particularly β2-antagonists, can inhibit MMP secretion and counteract MMP-related effects like invasion and migration. Strell et al. Norepinephrine enhances the adhesion of MDA-MB-231 breast cancer cells to human lung microvascular endothelial cells (HMVEC) through the GROα and β1-integrin pathways [49]. This process is similar to cancer cells extravasating to secondary metastatic sites.Thus, adrenergic receptor blockers can eliminate norepinephrine-induced effects. Sloan et al. showed in an in situ breast cancer mouse model that stress stimuli or pharmacological activation of the isoproterenol-sensitive adrenergic system increased distal organ metastasis by 30 times, likely mediated by macrophage infiltration into the primary tumor stroma [50]. Stress-induced macrophages tend to differentiate into an M2-like phenotype, expressing pro-metastatic genes linked to tumor invasion. At the same time, receptor blockers like propranolol and macrophage inhibitor GW2580 can significantly inhibit stress-induced metastasis [51]. The results indicate that stress hormones may trigger metastatic signals during carcinogenesis across various cancer types, and receptor blockers could effectively inhibit solid tumor metastasis.

Smoking and stress synergistically promote the growth of colon tumors [52]. Research in animal models of colon cancer indicates that β-blockers can inhibit NNK-induced colon cancer cell proliferation and counteract nicotine-induced epinephrine synthesis and release in these cells [52].

Dopamine receptors

Dopamine, a primary catecholamine neurotransmitter, is crucial in the central nervous system. D1- and D2-dopamine receptors (D1R and D2R) are the main excitatory and inhibitory receptors in the central nervous system, signaling through G protein Gs and G protein Gi, respectively [53]. Dysfunction in the dopaminergic system can lead to disorders such as schizophrenia and Parkinson’s disease.D1R and D2R are key therapeutic targets for Parkinson’s disease, schizophrenia, and various neuropsychiatric disorders. Research indicates that schizophrenia and Parkinson’s disease have distinct influences on various cancers, sometimes yielding divergent conclusions even within the same cancer type [53]. The results indicate a potential link between dopaminergic system imbalance and cancer development [54]. Research indicates that DRD1 positivity in breast cancer correlates with poor prognosis, whereas elevated DRD2 levels in pancreatic cancer can be targeted with DRD2 inhibitors to impede tumor growth via the ERK signaling pathway [55]. Sonam Dolma reported that DRD4 inhibition can obstruct autophagy and the proliferation of glioma stem cells [56]. DRD1 and DRD5 show varying expression in hepatocellular carcinoma (HCC), while thioridazine, a dopamine receptor antagonist, inhibits metastasis in HCC and proliferation in breast cancer [57]. The results suggest that dopamine and its receptors influence multiple cancer types.Increased local dopamine secretion has been observed in cholangiocarcinoma cell lines, promoting growth and indicating a dopaminergic system imbalance in HCC [57]. Dopamine enhances the proliferation and metastasis of hepatocellular carcinoma (HCC). High DRD1 expression in HCC tissues correlates with poor prognosis in patients [57]. DRD1 upregulation enhances liver cancer malignancy by activating the cAMP/PI3K/AKT/CREB pathway, promoting proliferation and metastasis, whereas its downregulation inhibits these processes [57]. Depleting DRD1 can counteract the effects of dopamine on HCC [57]. SCH23390, a DRD1 antagonist, suppresses HCC cell growth and spread in vitro and in vivo [57]. The results indicate that dopamine release within hepatocellular carcinoma enhances hepatocyte proliferation and metastasis. DRD1 contributes to HCC progression and acts as a key mediator in the dopaminergic system, making it a potential therapeutic target and prognostic biomarker for HCC [57]. Dopamine signaling is associated with anti-tumor immunity. Tissue-resident memory CD⁸⁺ T (TRM) cells contribute to strong protective anti-tumor immune responses and better cancer patient prognosis [58]. In a patient with colorectal cancer cohort, dopamine expression was positively associated with patient survival and CD8 + T-cell infiltration [58]. Thus, therapeutic strategies that modulate TRM cell production or activity may be effective in cancer treatment.

Dopamine may suppress tumor growth by activating the dopamine receptor D2 on both endothelial and tumor cells (Fig. 4). Various tumor cells express DRs and dopamine transporters. DRD2 agonists can affect tumor cell behavior. The DRD2 agonist bromocriptine inhibits the clonogenic growth of human small-cell lung cancer cells [59]. Pre-treatment with the DRD2 agonist quinpirole suppresses IGF1-induced proliferation of human gastric cancer cells by decreasing phosphorylation of the IGF1 receptor and the downstream molecule Akt [60]. In various animal experiments, the role of dopamine in cancer has been further studied. Tumor microvascular density and permeability were enhanced in dopamine-deficient mice, and tumor endothelial cell VEGF-R2 phosphorylation increased [61]. Dopamine transporter knockout mice display an enhanced dopaminergic system and increased systemic dopamine levels compared to dopamine-deficient mice [62]. Subcutaneous implantation of lung cancer cells in these mice resulted in smaller tumors and reduced microvascular density compared to wild-type mice [62]. In a mouse model of schizophrenia, APO-SUS rats had smaller breast tumor volumes, and tumor microvascular density was lower than in APO-UNSUS insensitive rats [63]. APO-SUS rats exhibited fewer lung metastases compared to APO-UNSUS rats following intravenous injection of breast cancer cells [63]. In some animal models, dopamine treatment led to reduced tumor growth and lower microvascular density [64, 65]. Dopamine decreased vascular permeability in mouse models of human colon and breast cancer, as well as in mouse ovarian tumors, resulting in reduced ascites accumulation in the ovarian model [64].

Fig. 4.

Platelets are responsible for storing and releasing both dopamine and serotonin. Dopamine, through DRD2 activation, suppresses VEGF-induced proliferation of endothelial cells and mobilization of EPCs. Serotonin promotes tumor cell proliferation through activation of specific receptors on diverse tumor types and enhances endothelial cell proliferation and migration via 5-HTR1 and 5-HTR2 activation

The role of DRD2 in animal experiments was also studied. DRD2 knockout mice with sarcoma or melanoma exhibited larger tumors, along with enhanced microvascular density and permeability, compared to wild-type mice [61]. The lack of effect of dopamine treatment on EPC mobilization in these mice indicates that DRD2 is crucial for dopamine’s functional activity. Bromocriptine and quinpirole, both DRD2 agonists, suppressed tumor angiogenesis in ovarian cancer within a mouse model [64]. Pre-treatment with DRD2 antagonists, such as eticlopride or domperidone, can negate dopamine’s inhibitory effects on gastric and ovarian tumor growth in mice and rats [65]. Dopamine-induced pericyte coverage was not affected by the DRD2 antagonist eticlopride [65]. Data from siRNA targeting experiments indicate that DRD2 activation can inhibit tumor cell proliferation. In stress-induced mice with SKOV3ip1 or HeyA8 ovarian tumors, co-administering dopamine alongside siRNA nanoparticles targeting mouse DRD2 in endothelial and other host cells nullified dopamine’s inhibitory impact. However, co-injecting dopamine with siRNA nanoparticles targeting human DRD2 present in tumor cells only suppressed HeyA8 ovarian tumor growth. These studies conclude that dopamine inhibits tumor growth by activating DRD2, which suppresses tumor angiogenesis, and in some tumors, DRD2-mediated inhibition of tumor cell proliferation may also contribute. The dopamine concentration in cancer patients has also been studied, with the concentration of dopamine and tyrosine hydroxylase in tumor tissue being lower than in benign tissue [61]. DRD2 is present in gastric cancer tissue and is an attractive target for DRD2 agonist therapy.

5-HT receptors

5-Hydroxytryptamine (5-HT), also known as serotonin, is a unique neurotransmitter that regulates numerous biological processes by activating up to 13 different receptors. These serotonin receptors are classified into seven different categories based on their structure and function. They are co-expressed across diverse tissues and cell types, all employing 5-HT as a ligand.Except for the 5-HTR3 subfamily, most receptors are G protein-coupled receptors (GPCRs). These receptors activate four major interconnected signaling networks: PI3K/Akt, PKC/Ca²⁺, MAPK, and PKA-cAMP. In contrast to the inhibitory effects mediated by dopamine acting on its receptor DRD2, 5-HT and its specific receptors promote tumor cell proliferation and migration (Fig. 4).

Immune cells engage with the nervous system in the tumor microenvironment and secondary lymphoid organs through 5-HT and its receptors (5-HTRs), affecting tumor progression [66]. Serotonin signaling has diverse effects on the immune system [66]. It can stimulate T cell activation and proliferation, promote dendritic cell (DC) maturation, support B cell development, enhance natural killer (NK) cell cytotoxicity, and induce macrophage polarization to the M2 phenotype [66]. At the same time, serotonin signaling inhibits the polarization of M1 macrophages [66]. Serotonin’s varied impacts on immune cells position it as a crucial focus in tumor immunology research. Research suggests that the 5-HTR2B and 5-HTR7 signaling pathways facilitate the development of M2 macrophages, known for their anti-inflammatory characteristics, thereby promoting tumorigenesis [67]. Nocito et al. conducted a study using a mouse model of colon cancer [68]. Serotonin was observed to decrease matrix metalloproteinase 12 (MMP12) expression in macrophages, thereby aiding tumor progression through enhanced angiogenesis [68]. MMP12 has anti-angiogenic effects because it can cleave plasminogen into the angiogenesis inhibitor angiostatin. In tumors, 5-HTR2B expression is increased on M2 tumor-associated macrophages (TAMs) adjacent to VE-cadherin-positive endothelial cells [67]. This indicates that serotonin could enhance angiogenesis by influencing vascular development, potentially through 5-HTR2B signaling, aided by adjacent macrophages [67]. Serotonin facilitates the maturation and chemotaxis of bone marrow-derived dendritic cells (BMDCs) and supports the development of anti-inflammatory dendritic cells, potentially influencing T cell polarization towards a regulatory phenotype [66]. Regulatory T cells typically suppress the activity of cytotoxic T cells, thereby promoting tumor development. Serotonin signaling generally appears to support tumor progression by suppressing anti-tumor immune responses. Modulating the serotonergic system with various antipsychotic drugs and chemicals could significantly impact tumor immunity regulation.

Serotonin receptor agonists and antagonists modulate signaling by either stimulating or inhibiting various 5-HTRs. Chemical agonists and antagonists are essential for understanding serotonin’s role via various receptor subtypes in tumor immunity. Certain agonists and antagonists are broad-spectrum, capable of targeting multiple receptor subtypes. The agonists 8-OH-DPAT (5-HTR1A/7), 2-methylserotonin (5-HTR3), 2-MHT (5-HTR4), and 5-CI increase IL-8 and IL-1β release in dendritic cells [66]. Agonists like AnHcl (5-HTR1B), BRL5443 (5-HTR1E/1F), and DOI (5-HTR2) also activate dendritic cells [66]. The anti-inflammatory properties of macrophages are enhanced by the 5-HTR2B agonist BW-723C86 and the 5-HTR7 agonist AS19 [66]. 5-HTR3 agonist 2-methylserotonin and 5-HTR7 agonist AS19 help activate and further proliferate T cells [66]. SB-269,970 and SB-258,729 are prominent antagonists that inhibit serotonin signaling via 5-HTR7 and have been extensively researched [66]. These antagonists can inhibit the differentiation of anti-inflammatory M2 macrophages, modulate cytokine release in dendritic cells, and suppress ERK signaling in T cells [66]. Serotonin receptor antagonists like methysergide and ketanserin can suppress dendritic cell activation and prevent T cells from initiating delayed-type hypersensitivity responses [66]. The 5-HTR1A antagonist SB-216,641, along with other antagonists, exhibits effects on T cells comparable to those of SB-269,970 and SB-258,729 [66]. Research indicates that serotonin receptor agonists and antagonists show significant potential as immune cell regulators, offering promising therapeutic applications in diseases like cancer.

GABA receptors

Gamma-aminobutyric acid (GABA), the primary inhibitory neurotransmitter in the central nervous system, is extensively found in peripheral endocrine organs like the pituitary gland, adrenal medulla, and gastrointestinal tract, as well as in non-neural tissues, including cancer. GABA receptors are categorized into three types: ionotropic GABAA and GABAC receptors, and metabotropic GABAB receptors. GABAA and GABAC receptors are oligomeric chloride ion channels, composed of heterogeneous complexes made up of five subunits.GABRP, the π subunit of the GABAA receptor, modulates the sensitivity of recombinant receptors to modulators. The study identified GABRP as a differentially expressed factor initiating tumors in pancreatic ductal adenocarcinoma (PDAC). GABRP has been identified as a carcinogenic factor in multiple cancers, including breast, pancreatic, and ovarian cancers [69].

Pancreatic ductal adenocarcinoma (PDAC) ranks among the top causes of cancer mortality globally. Adding GABA to the cell culture medium specifically enhances the proliferation of GABRP-expressing PDAC cells, while GABRP-negative cells remain unaffected [70]. The growth-promoting effects of GABA can be inhibited by GABAA receptor antagonists. GABA treatment promoted growth in a model of HEK293 cells expressing exogenous GABRP [70]. The results suggest that GABA and GABRP are crucial in the onset and advancement of PDAC, presenting this pathway as a potential molecular target for novel PDAC therapies [70]. Research utilizing tumor genome maps and gene expression databases has revealed the distinct expression pattern of the γ-aminobutyric acid A-type receptor π subunit (GABRP) in human and mouse PDAC tissues and cells [71]. Through subcutaneous transplantation and lung metastasis models, the in vivo impact of GABRP on PDAC was evaluated [71]. The study found that GABRP expression was markedly increased in PDAC tissues, correlated with poor prognosis, and facilitated tumor growth and metastasis [71]. GABRP expression in PDAC is associated with macrophage infiltration, and pharmacological removal of macrophages significantly reduces GABRP’s carcinogenic role in PDAC [71]. Therefore, overexpressed GABRP demonstrates an immune-modulatory effect independent of neurotransmitters in PDAC [71]. Targeting GABRP or its interacting partner KCNN4 could be an effective strategy for treating PDAC.

Research indicates that the GABAA receptor α3 subunit (Gabra3), usually found in the adult brain, is also present in breast cancer [72]. High levels of Gabra3 expression are associated with reduced survival rates in breast cancer patients, paralleling findings in pancreatic cancer studies. Research indicates that Gabra3 activates the AKT pathway, facilitating breast cancer cell migration, invasion, and metastasis [72].

Glutamic pyruvate transaminase (GPT2) facilitates a reversible transamination between alanine and α-ketoglutarate (α-KG), producing pyruvate and glutamate, with the latter capable of converting to γ-aminobutyric acid (GABA) [73]. A study utilized a tail vein model and a breast-specific Gpt2-/- spontaneous tumor mouse model to evaluate Gpt2’s role in breast cancer metastasis in vivo [73]. The study found that GPT2 overexpression elevated GABA levels, facilitating breast cancer metastasis through GABAA receptor activation. In both xenograft and transgenic mouse models, GABRD was essential for GPT2/GABA-driven breast cancer metastasis [73]. Gpt2 knockout in genetically modified Gpt2-/- breast cancer mice decreased lung metastasis and extended the overall survival of tumor-bearing mice [73]. This indicates that GPT2 facilitates breast cancer metastasis via the GABA-activated GABAR-PKC-CREB signaling pathway and could be a potential target for breast cancer treatment.

Glycine receptors

Glutamate binding to its receptors can promote tumor cell proliferation, survival, and invasiveness [74]. Functional chemical synapses exist between presynaptic neurons and postsynaptic glioma cells, displaying typical synaptic ultrastructure above tumor microtubules and producing postsynaptic currents via AMPA glutamate receptors [75]. Neuronal activity, including epilepsy, can trigger synchronized calcium transients in the glioma network connected to the tumor microtubules [75]. Targeting glioma-specific AMPA receptors genetically can decrease calcium-dependent tumor cell invasiveness and inhibit glioma progression [75]. Anesthesia and the AMPA receptor antagonist Perampanel also reduce invasion and growth [75]. These findings demonstrate direct synaptic interactions between neurons and glioma cells, highlighting their biological and potential clinical significance.

Varun et al. investigates whether neuronal glutamate signaling (NGS) affects the proliferation of tumor cells and the overall progression of gliomas [75]. Optogenetic transduction of glioblastoma (GB) cells in monoculture was used to simulate synaptic stimulation [75]. During this process, light stimulation triggered a proliferative response in the tumor cells [75]. In vivo imaging revealed that the growth dynamics of GB cells co-transduced with tdTomato and GluA2DN-GFP were significantly reduced compared to GB cells expressing only tdTomato without AMPAR interference [75]. However, similar growth dynamics were observed in monoculture in vitro. Further in vitro experiments confirmed that the growth inhibition effect of AMPAR blockers depended on the presence of neurons [75]. Perampanel, a selective non-competitive AMPAR antagonist and approved anticonvulsant, shows promising anti-tumor effects in glioma patients, meriting additional research. Long-term Perampanel administration in xenografted mice reduced GB cell proliferation in vivo, as observed through tumor imaging over time, independently of in vitro assay results [75]. In summary, inhibiting AMPAR signaling through genetic and pharmacological methods, along with disrupting neuron-GB cell synaptic communication via NGS, can decrease GB cell malignancy and slow glioma progression [75].

The NMDAR glutamate receptor enhances invasive tumor progression in both neuroendocrine and ductal pancreatic cancers [76]. Glutamate’s autocrine activation engages an NMDAR with GluN1 and GluN2B subunits, where GluN2B includes a key phosphorylation site essential for NMDAR signaling. This process is mediated by the cytoplasmic linker protein GKAP, triggering invasive growth programs marked by extensive alterations in cellular regulatory pathways [76]. In brain metastasis (B2BM), it was found that B2BM cells jointly selected a recently identified neuronal signaling pathway involving activation of glutamate ligands of NMDA receptors (NMDARs), a key mechanism for brain metastasis colonization, and associated with poor prognosis [77]. In certain primary tumors, NMDAR is activated autocrinely, with both human and mouse B2BM cells expressing the receptor [77]. However, the secreted glutamate does not trigger signal transduction directly; rather, it establishes a pseudo-triple synapse between cancer cells and glutamatergic neurons, underpinning a key mechanism for brain metastasis [77].

GRM1 is part of the glutamate receptor family, which includes ionotropic (iGluR) and metabotropic (mGluR) receptors. L-quisqualate acts as an agonist for group I metabotropic glutamate receptors (mGluRs). LY367385 or BAY36-7620 is identified as a competitive or noncompetitive antagonist of GRM1. These drugs played a vital role in previous research on GRM1 signaling in mouse melanoma cell lines [78]. Research indicates that the GRM1 agonist L-quisqualate activates mitogen-activated protein kinase (MAPK) in mouse melanoma cell lines [78]. The anti-proliferative effects of iGluR antagonists have been evaluated across multiple cancer types, such as breast, colon, gliomas, and lung cancers [79]. Treatment with iGluR antagonists can inhibit tumor cell proliferation and motility [79]. Dizocilpine, an iGluR antagonist, can suppress metastatic lung adenocarcinoma growth by inhibiting the MAPK signaling pathway [80]. In human melanoma cells expressing GRM1, treatment with GRM1 antagonists (LY367385 or BAY36-7620) or glutamate release inhibitors (riluzole) can suppress cell proliferation and decrease extracellular glutamate levels [81].

Histamine receptors

Histamine has been identified as a neurotransmitter in the brain, involved in regulating sleep and wakefulness, hibernation, feeding and drinking behaviors, as well as the functions of the autonomic nervous system and endocrine system [82]. Histamine H1 and H2 receptors are commonly found in nerve, glial, and endothelial cells, while H3 receptors are primarily located on neurons [82]. In experimental brain tumor models that mimic human brain tumors, histamine enhances the permeability of experimental brain tumors and adjacent areas, with both H1 and H2 receptors identified in these tumors [82]. Numerous studies have explored the histamine signaling mechanisms derived from brain tumor cell lines.

Potentially, histamine could be a key factor in brain tumors, as these tumors rely on a sufficient blood supply [83]. In general, histamine in blood vessels induces endothelial gap formation and depolarization of endothelial cells. Additionally, histamine increases intracellular Ca²⁺ levels via the H1 receptor mechanism [82]. Research on rats with C6 glioma transplants demonstrated that carotid artery infusion of histamine elevated blood flow to the tumor and adjacent brain regions, whereas H1 antagonists like pyrilamine and H2 antagonists like cimetidine diminished the histamine-induced blood flow response [82]. Histamine infusion into the carotid artery with Evans blue led to selective extravasation in tumors and adjacent brain tissue [82]. Radioautographic studies on rats with RG2 glioma cell transplants demonstrated that histamine notably enhanced tumor permeability, an effect counteracted by cimetidine [82]. The effects of histamine on the migration, proliferation, and differentiation of developing brain cells are still unclear. However, cimetidine can induce migration of human brain tumor cells in vitro, while histamine inhibits this migration. Cimetidine potentially inhibits proliferation in three out of five cell lines, likely due to its interaction with H2 receptors [82]. HRH1 has an immunosuppressive role in tumor cells [82]. Therefore, HRH1 intervention may be a promising approach to enhance pancreatic ductal adenocarcinoma (PDAC) response to immunotherapy. H1/H2 histamine receptors antagonists reduced tumor growth, serum HA, angiogenesis, and EMT [84]. In vitro, H1/H2 histamine receptors blockers inhibited bile duct proliferation, along with proliferation, angiogenesis, EMT, and migration in cholangiocarcinoma cells [84]. Inhibiting H1/H2 histamine receptors can mitigate Primary Sclerosing Cholangitis-related damage and decrease cholangiocarcinoma growth, angiogenesis, and EMT [84]. Considering the risk of cholangiocarcinoma development in Primary Sclerosing Cholangitis patients, histamine receptors blockade could offer therapeutic benefits for these conditions [84].

Opioid receptors

Opioids and the somatostatin system are two major inhibitory regulatory systems in mammals, involved in regulating various physiological processes from hormone secretion to cell proliferation. Opioid substances and receptors have been identified in various human primary tumors and cancer cell lines [85].

Endogenous opioid peptides are derived from three different precursor proteins: preproenkephalin (PENK), preprodynorphin (PDYN), and prepro-opiomelanocortin (POMC) [85]. Opioid receptors belong to the seven-transmembrane receptor superfamily and are pharmacologically and biochemically divided into three major types: µ, δ, and κ. Opioid peptides bind to opioid receptors, inhibiting the activity of adenylate cyclase, thus reducing intracellular cAMP levels [85].

In most studies, opioid peptides exhibit inhibitory effects on malignant cell growth. However, the exact mechanisms linking opioid peptide action with carcinogenic events are not fully understood. Opioid peptides bind to opioid receptors expressed on the cell surface, thereby affecting growth factor signaling pathways. However, other highly homologous receptors within the same superfamily may also co-express on tumor cell membranes, suggesting that some effects, such as anti-proliferation, might also be mediated through pathways outside the opioid binding sites. The interaction between opioid peptides and somatostatin receptors has shown significance in breast cancer, prostate cancer, and renal cancer. Other direct mechanisms include interactions with cytoskeletal components, or lowering steroid receptor levels and affecting steroid-regulated enzyme secretion. Indirect mechanisms involve regulation of hormone release that controls tumor growth. Opioid peptides may also indirectly affect growth by regulating the immune system; they have been shown to modulate lymphocyte proliferation and cytotoxic activity of natural killer cells, inhibit antibody production in human lymphocytes through interaction with high-affinity cell surface receptors, and bind to the terminal complex of the complement system. The cellular opioid system, including opioid receptors and opioid peptides, is responsible for tumor-suppressing functions, and may become inactivated in cancer cells. Possible inactivation mechanisms include the absence of bioactive opioid peptides or their receptors, or the presence of factors inhibiting their functions [86]. Nicotine, as an opioid antagonist in lung cancer cells, may be one of these inhibitory factors. Surprisingly, opioid peptides have also been shown to promote tumor growth by increasing cell proliferation or affecting tumor blood flow. Dynorphin A stimulates the proliferation of prostate cancer cells (DU145). Met-enkephalin enhances proliferation in human neuroblastoma cells, whereas β-endorphin promotes growth in small-cell lung cancer cell lines [87]. Studies by Iishi et al.showed that prolonged use of OGF (an opioid peptide) promoted colon tumor development, while the opioid receptor antagonist naloxone inhibited this effect [88]. The precise mechanisms through which opioid peptides promote cell proliferation are not yet understood. Opioid peptides may also promote carcinogenesis through indirect pathways. For example, LVV-hemorphin-7 from hemorphins inhibits angiotensin-converting enzyme through a non-competitive mechanism, prolonging the half-life of vasoactive bradykinin and ultimately increasing blood flow to the tumor at the expense of host tissue [89]. Bradykinin may also act as a nutrient factor in some tumors, stimulating malignant cell growth [90].

Antipsychotic drugs and cancer

Despite advancements in cancer treatment over recent decades, patient survival rates have not significantly improved [91]. This highlights the urgent need for new cancer treatments and drugs. Research indicates that antipsychotic drug treatment is associated with a reduced incidence of cancers, such as prostate, breast, and colorectal cancer, in both genders [92]. Antipsychotic drugs have been proposed for use in the treatment regimens of various cancers (Table 1). Experts, including Rahman, suggest using antipsychotics such as ziprasidone, asenapine, quetiapine, clozapine, and aripiprazole for breast cancer treatment, but advise against risperidone, paliperidone, and fluphenazine [93]. Among second-generation antipsychotics, risperidone, paliperidone, and fluphenazine exhibit poor blood-brain barrier (BBB) penetration. Consequently, higher serum concentrations are required compared to other antipsychotics to achieve therapeutic CNS levels, which may lead to unforeseen risks despite attaining clinical efficacy [93]. Many antipsychotic drugs, including thioridazine, trifluoperazine, phenothiazine, sertindole, chlorpromazine, pimomazine, fluphenazine, and promazine, are associated with various types of cancer. While nearly all antipsychotic drugs demonstrate cytotoxicity, phenothiazine-class antipsychotics are notably more effective in cancer treatment than other related drugs. These drugs demonstrate antiproliferative properties in various cancers, such as lymphoblastic lymphoma, astrocytoma, melanoma, neuroblastoma, and breast adenocarcinoma [94]. Research also shows that several antipsychotic drugs can reverse multidrug resistance by inhibiting P-glycoprotein, without causing significant adverse effects [95]. At safe doses, some dopamine receptor agonists like aripiprazole exhibit significant effects in inhibiting cancer stem cells (CSCs), spheroid formation, and chemotherapy resistance, while also showing good efficacy in promoting cell differentiation [96].

Table 1.

Psychiatric drugs with potential anti-neoplastic effects

Conclusions and future directions

Recently, cancer neuroscience has emerged as a rising field of study, with research dynamics steadily gaining momentum. Current data suggest that the nervous system significantly influences the initiation, progression, dissemination, and treatment resistance of cancer, enhancing our modern comprehension of cancer biology.

Despite being in its early stages, cancer neuroscience research has produced groundbreaking findings that underscore the importance of studying the interaction between the nervous system and cancer. To date, for each type of cancer studied, there is evidence of its interaction with the central nervous system or peripheral nervous system, which may promote or occasionally suppress cancer progression. With a clearer understanding of cancer mechanisms, a key question arises: will the interaction between the nervous system and cancer be universally acknowledged as a fundamental principle in cancer development? In the future, we anticipate significant discoveries concerning established cancer neuroscience mechanisms. Additionally, investigating glial cell functions in both central and peripheral nervous systems, along with the impact of neural innervation on the tumor microenvironment, will enhance our understanding and improve treatment strategies.

The search for new anti-cancer drugs is an extremely challenging task. To identify the best drug candidates for cancer treatment, existing drug screening technologies urgently need further expansion and improvement. Nevertheless, given that some promising antipsychotic DR antagonists have led us to a new chapter in cancer drug discovery, it is only a matter of time before we uncover candidates from existing drug libraries. Drugs like thioridazine serve as an ideal example, as it has been approved by the FDA and can be conveniently used in clinical research. Compared to newly developed drugs, these approved drugs have significant advantages in terms of cost and time. However, drug repurposing may require safety approval. Similar to thioridazine, other drugs that act on the nervous system should also receive equal attention in the search for new cancer treatment candidates. Trifluoperazine (TFP) targets calmodulin, dopamine receptors, and stress-response proteins. Through these mechanisms, it inhibits tumor growth, sensitizes tumors to chemoradiotherapy, and prolongs survival in xenograft animal models. Notably, TFP exhibits low toxicity toward healthy neurons and glial cells, highlighting its potential for repurposing as a therapeutic option for glioblastoma. Phenothiazine (PTZ) derivatives exhibit potent cytotoxicity against tumor cells, thereby demonstrating anticancer activity. Interestingly, PTZ is utilized as an antiemetic for chemotherapy-induced vomiting, potentially generating combined antitumor effects. Among their cytotoxic mechanisms, the modulatory effects of these drugs on autophagy have been emphasized. Consequently, the application of PTZ derivatives in anticancer chemotherapy may be regarded as a repurposing strategy. Furthermore, altering the structure of these drugs can improve our comprehension of their mechanisms and target interactions, potentially leading to the identification of new effective candidates. In the field of differentiation therapy, there are still many challenges. Although many drug candidates show good potential for inducing differentiation in preclinical models, very few can be applied clinically.

Although numerous tasks persist in cancer neuroscience, this research direction is anticipated to enhance treatment outcomes for various malignancies.In the future, cancer treatment methods should be integrated therapies, rather than monotherapies.

Author contributions

Yongxiang Zhao initiated the idea and supervised the whole process. Yongnian Li wrote the draft. Jintong Na reviewed the draft. Yongxiang Zhao and Liping Zhong made critical revisions to the draft.

Funding

This work was supported by Guangxi Science and Technology Major Program (No. AA24263028).

Data availability

No datasets were generated or analysed during the current study.

Declarations

Ethics and consent to publish

Not applicable.

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Not applicable.

Competing interests

The authors declare no competing interests.