Targeting molecular pathways in neuropathic cancer pain: from mechanisms to novel therapeutics
Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Health Science Center, Ningbo University, Ningbo, Zhejiang 315211, China
∗Corresponding author xiyang@nbu.edu.cnSummary
Neuropathic cancer pain (NCP) remains a formidable clinical adversary, severely compromising the quality of life for cancer survivors. Its pathogenesis is highly complex and multifactorial, bifurcated into tumor-induced and chemotherapy-induced neuropathic pain. This review dissects the intricate molecular mechanism of NCP, highlighting how the tumor microenvironment orchestrates neuro-tumor interaction. Bridging the gap between pathogenesis and treatment, we evaluate the vanguard of therapeutic strategies designed to breach the current therapeutic impasse. We specifically explore the potential of antisense oligonucleotides in silencing pathological gene expression, the deployment of nanotechnology for bespoke drug delivery, the targets of neuro-tumor interactions, and the modulation of the endocannabinoid system as a novel analgesic target. In summary, by integrating pathogenic insights with therapeutic innovations, this review aims to catalyze a paradigm shift, from symptomatic management to mechanism-based precision intervention, paving the way for a new epoch in NCP management.
Graphical abstract
Teaser
Oncology; Therapeutics
Introduction
Neuropathic cancer pain (NCP) stands as a formidable clinical adversary in modern oncology. Amidst the global rise in cancer incidence, NCP persists as an inextricable shadow, severing patients from recovery.1 Crucially, NCP is not a single disease entity but a complex pathology encompassing two distinct etiologies: tumor-induced neuropathic pain and treatment-induced neuropathic pain.2,3
Although the basic research has identified therapeutic molecular targets such as the exchange protein directly activated by cyclic adenosine monophosphate (EPAC1)4 and NF-E2 related factor 2 (Nrf2),5 current clinical management remains at a therapeutic impasse. Conventional analgesics, restricted by a “one-size-fits-all” paradigm, frequently fail to address the underlying heterogeneity of NCP.2 Furthermore, while emerging therapeutic strategies have evolved rapidly, such as antisense oligonucleotides (ASO), nanotechnology-based drug delivery systems, neuro-tumor therapies, and endocannabinoid system (ECS), they are largely studied in isolation, lacking a comprehensive framework to combine these novel technologies with specific pain mechanisms.6,7,8,9
Therefore, we aim to bridge the critical disconnect between isolated technological innovations and their precise application in mechanism-based pain management. By synthesizing the fragmented landscape of NCP, this review dissects the intricate NCP molecular mechanisms. Leveraging these mechanistic insights, we navigate the vanguard of therapeutic innovation, ranging from the ASO and the nanotechnology-based delivery systems to the modulation of the neural-tumor targets and ECS. Ultimately, by connecting these distinct dots, we advocate for a transition from the blunt tools of systemic analgesia to the scalpel of mechanism-based precision intervention.
Mechanisms of tumor-induced neuropathic pain
Globally, cancer cases were reported to be approximately 20 million in 2022 and are expected to approach 35 million by 2050.10 Amidst the increasing cancer burden, the challenge of tumor-induced neuropathic pain has garnered considerable attention.
Schwann cells in tumor-induced neuropathic pain
Schwann cells (SCs), the primary glial cell type of the peripheral nervous system, are widely distributed throughout various anatomical regions of the body and constitute approximately 90% of the endoneural space.11 These cells play a critical role in modulating tumor microenvironmental changes and immune reactions through the secretion of multiple factors, thereby facilitating tumor invasion into nerves and distant metastasis, which ultimately contributes to increased pain severity.
In the pancreatic ductal adenocarcinoma (PDAC) microenvironment, cancer cells induce the shift of SCs from a dormant to an activated condition through the release of interleukin-6 (IL-6).11 SCs influence cancer cells by secreting transforming growth factor β (TGF-β) and L1 cell adhesion molecule (L1CAM), leading to neural infiltration.11 Additionally, SCs recruit tumor-associated macrophages (TAMs) by releasing interleukin-33 (IL-33) and C-C motif chemokine ligand 2 (CCL2), with CCL2 binding to chemokine receptor 2 (CCR2) on macrophages, inducing the secretion of cathepsin B by TAMs, thereby further promoting neurological injury.11 In lung cancer, Schwann cell transcriptomics show increased expression of CCL2, C-X-C motif chemokine ligand 5 (CXCL5), CXCL8, and CXCL12. CCL2 produced by SCs promotes the M2 polarization of macrophages, thereby increasing the proliferation of lung cancer cells.12 In breast cancer, the redox effector-1 (Ref-1) secreted by cancer cells activates SCs through the hypoxia inducible factor-1α (HIF1α)/ROS pathway, leading to an increase in CXCL2 production, and CXCL2 from SCs induces macrophage infiltration around peripheral nerves, ultimately triggering spontaneous nociception and pain perception.13
Tyrosine receptor kinase A-dependent transient receptor potential channel in tumor-induced neuropathic pain
Perineural invasion (PNI) refers to the pathological phenomenon in which cancer cells infiltrate and spread along peripheral nerves. As a key pathological feature of various malignancies, PNI is commonly observed in cancers such as pancreatic cancer, breast cancer, and colorectal cancer.14 PNI serves as both a significant indicator of disease progression and a key contributor to pain initiation and intensification.
Cytokines and growth factors released by cancer cells and nerves play a crucial role in the pain mechanisms associated with PNI. In pancreatic cancer, interaction between nerve growth factor (NGF) and tyrosine receptor kinase A (TrkA) activates several pathways, including the MAP kinase-extracellular signal regulated kinase (MAPK-ERK) and phosphatidylinositol 3-kinase (PI3K) pathways,15 which activate downstream protein kinase C (PKC) and increase the sensitivity of the transient receptor potential vanilloid 1 (TRPV1) channel, thereby lowering its activation threshold.16 Additionally, PI3K mediates the conversion of phosphatidylinositol-(3,4)-P2 (PIP2) to PIP3.17 This conversion promotes the activation of TRPV1.16 The activation of PI3K triggers the SRC tyrosine protein kinase, promoting the transport of transient receptor potential ankyrin 1 (TRPA1) and TRPV1 to the cell membrane. These signaling mechanisms lower the activation threshold of transient receptor potential (TRP) channels, ultimately contributing to symptoms such as nociceptive hypersensitivity and abnormal pain.16 The activation of TRPV1 leads to neuronal depolarization and the release of pain-associated neurotransmitters, including calcitonin gene-related peptide (CGRP) and substance P.15,18 These neurotransmitters transmit pain signals to the central nervous system and contribute substantially to the intensification of pain in oncology patients (Figure 1).
Role of GABAergic inhibition in tumor-induced neuropathic pain
One of the key mechanisms underlying the initiation and maintenance of tumor-induced neuropathic pain is the disruption of GABAergic inhibition within the central nervous system (CNS). Gamma-aminobutyric acid (GABA) receptors, the principal inhibitory neurotransmitter receptors in the CNS, maintain the dynamic balance between excitatory and inhibitory synaptic transmission.19 However, tumor-associated pathological conditions impair this inhibitory system at multiple levels.
Evidence indicates that, under cancer conditions, the expression of gamma-aminobutyric acid transporter-1 (GAT-1) is significantly upregulated in astrocytes, and elevated GAT-1 expression enhances the efficiency of GABA reuptake from the synaptic cleft, thereby reducing the effective concentration of GABA available for synaptic signaling.20 This decrease in synaptic GABA weakens inhibitory neurotransmission in the spinal dorsal horn and contributes to the persistent maintenance of pain.20 In addition, the research demonstrated in a cancer-induced bone pain (CIBP) model that gamma-aminobutyric acid B (GABAB) receptor protein expression in spinal dorsal horn neurons is downregulated in a time-dependent manner.21 The attenuation of GABAB receptor function not only weakens receptor-mediated postsynaptic inhibitory effects but may also relieve the inhibition of adenylyl cyclase, thereby activating the cyclic adenosine monophosphate (cAMP) and protein kinase A (PKA)–cAMP response element-binding protein (CREB) signaling pathway, which is critically involved in the development and maintenance of chronic pain.21 Furthermore, accumulating research highlights a close interaction between the GABAergic system and neuroinflammation. The research reported in a nerve injury model that the expression of the GABAA receptor α2 subunit (GABRA2) was markedly downregulated across multiple pain-related brain regions, concomitant with elevated levels of the proinflammatory cytokines tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β).22 Further analyses demonstrated that the selective silencing of GABRA2 resulted in an additional increase in inflammatory cytokine levels, suggesting that GABRA2 exerts an inhibitory regulatory effect on inflammatory responses.22 Under tumor-associated inflammatory conditions, downregulation of GABRA2 may weaken GABAA receptor-mediated chloride influx and neuronal hyperpolarization,23 and, by relieving constraints on neuronal excitability and inflammatory processes, synergistically amplify pain signaling, thereby facilitating the development of tumor-induced neuropathic pain.22
Tumor microenvironment in tumor-induced neuropathic pain
Neuronal regulation of cancer-associated fibroblasts in tumor-induced neuropathic pain
Emerging evidence suggests that neurons promote tumor proliferation by establishing interactions with cancer-associated fibroblasts (CAFs). The sympathetic nervous system plays a crucial role in maintaining immunosuppression in PDAC. Neuronal signals inhibit the immune-activating potential of CAFs, thus sustaining an immunosuppressive tumor microenvironment (TME).27 When denervation was performed using 6-hydroxydopamine (6-OHDA), the biological properties of CAFs were altered, including the upregulation of the interferon-alpha (IFN-α) response pathway, genes related to allograft rejection, and pro-inflammatory factors such as TNF and IL-1β. This alteration contributed to the remodeling of the immune microenvironment. Moreover, denervation led to a significant increase in the number of tumor-infiltrating CD45+ immune cells, thereby reversing the immunosuppressive state of the tumor.27
Research indicates that within the PDAC microenvironment, CAFs secrete NGF, which induces nociceptive neurons to release CGRP. The released CGRP triggers the RAMP1 signaling pathway in CAFs, suppressing IL-15 expression. The suppression of IL-15 reduces NK cell infiltration and weakens their cytotoxic function, thereby promoting PDAC progression and tumor-induced neuropathic pain.28
CD8+ immune cell exhaustion in tumor-induced neuropathic pain
In a mouse model of malignant melanoma, it was found that CGRP released by tumor-associated injury-sensing neurons functions through the RAMP1/CALCRL receptor signaling pathway.24 Further research revealed that the CGRP-RAMP1 signaling pathway directly results in the functional depletion of CD8+ T cells, a phenomenon particularly prominent in melanoma models. Blocking CGRP-RAMP1 signaling with specific antagonists, such as Rimegepant, effectively reversed the immune depletion phenotype, inhibited tumor progression, and significantly enhanced the therapeutic effects of other antitumor drugs.29 It has been reported that IL-13 produced by CD8+ T cells stimulates macrophages to secrete IL-10, thereby contributing to the alleviation of Chemotherapy-induced peripheral neuropathy.30 By suppressing the production of pro-inflammatory cytokines from macrophages and dendritic cells, IL-10 blocks T cell activation and promotes an anti-inflammatory state, ultimately leading to the relief of neuropathic pain.30 Therefore, CD8+ T cell exhaustion not only impairs immune function but also exacerbates the development of tumor-induced neuropathic pain.
Immune checkpoint molecules are key regulators of tumor immune evasion. Within the TME, tumor-associated nerve fibers have been shown to express programmed death ligand 1 (PD-L1), which interacts with programmed death 1 surface receptor (PD-1), thereby suppressing T cell activation and promoting immune escape.31 In prostate cancer, PD-L1 expression has been identified on intratumoral nerve fibers, and a higher density of PD-L1+ fibers is associated with the decreased infiltration of CD8+ T lymphocytes, suggesting that tumor-associated nerves may contribute to local immune suppression through the PD-L1/PD-1 signaling pathway.31 Upregulation of the PD-L1/PD-1 signaling pathway leads to impaired CD8+ T cell function, which disrupts the immune-inflammatory cascade and limits the spread of inflammation at the injured site, thereby alleviating tumor-induced neuropathic pain. In contrast, blocking PD-1 results in an increase in TNF-α production by CD8+ T cells, restoring their pro-inflammatory function and accelerating the inflammatory response, which ultimately contributes to tumor-induced neuropathic pain.32
Macrophage polarization in tumor-induced neuropathic pain
TAMs, representing more than 50% of tumor-infiltrating immune cells, are pivotal components of the TME.33 These macrophages exhibit remarkable plasticity, enabling them to adopt different phenotypes in response to various stimuli within the tumor microenvironment, primarily classified into pro-inflammatory M1 macrophages and anti-inflammatory M2 macrophages.34 In the early stages of tumorigenesis, TAMs predominantly present the M1 phenotype, exerting potent anti-tumor activity. However, as the tumor progresses, cancer cells secrete a range of immune regulatory factors, including IL-10, CXCL12, vascular endothelial growth factor (VEGF), CCL2/3/4/5/7/8, and platelet-derived growth factor (PDGF). These factors gradually hijack the immune response, recruiting circulating monocytes and M0 macrophages to the TME, prompting their transformation into M2 macrophages.35
The primary glial cells of the peripheral nervous system, SCs, facilitate the recruitment of myeloid-derived suppressor cells (MDSCs) and enhance their immunosuppressive functions. SCs release CCL2 into the TME, prompting the transformation of TAMs into the M2 phenotype, thereby suppressing anti-tumor immune responses.31 As tumor progression continues, the proportion of M2 macrophages increases, eventually becoming the dominant phenotype within the TME. M2 macrophages play a critical role in tumor growth, metastasis, and immune evasion. Tumor cells secrete the chemokine CCL1, which causes the gradual replacement of M1 macrophages by M2 macrophages.35 Additionally, Th2 cells and regulatory T cells, which express the CCR8 receptor, are recruited by CCL1, further establishing and maintaining an immune-suppressive microenvironment that promotes tumor growth.
Due to the heterogeneity of macrophages, M1 macrophages promote the onset of pain by secreting cytokines, including TNF-α and IL-1β. In contrast, M2 macrophages secrete cytokines such as IL-10 and TGF-β, playing a role in suppressing inflammation.36 Therefore, Pharmacological modulation of macrophage polarization from the pro-inflammatory M1 to anti-inflammatory M2 phenotype may represent a promising therapeutic strategy for pain management (Figure 2).
Mechanisms of chemotherapy-induced neuropathic pain
Chemotherapy-induced neuropathic pain is a clinically challenging issue. The peripheral nervous system (PNS) lacks the protection of the blood-brain barrier (BBB), which makes peripheral neurons more susceptible to direct toxicity from antitumor drugs.37 Understanding the mechanisms underlying chemotherapy-induced neuropathic pain is crucial for developing effective therapeutic agents to prevent or treat this debilitating side effect.
Given the wide variety of neurotoxic chemotherapeutic drugs, an exhaustive classification is beyond the scope of this review. Therefore, we specifically focus on two clinically prevalent classes: platinum and doxorubicin. We aim to elucidate the shared and distinct molecular mechanisms underlying chemotherapy-induced neuropathic pain, such as oxidative stress and mitochondrial dysfunction. By highlighting these key pathways, we intend to provide a theoretical foundation for identifying promising therapeutic targets.
Mechanisms of platinum-induced neuropathic pain
Platinum-based compounds, such as cisplatin, constitute a class of metal-based chemotherapeutic drugs with substantial clinical value in oncology and have become critical in the treatment of various malignant tumors.
Platinum-based drugs act by forming DNA adducts that interfere with DNA replication and repair processes in tumor cells, leading to apoptosis and cell death.38 The dorsal root ganglion (DRG) neurons are often unable to effectively remove DNA-platinum adducts, which hinder the transcription of ribosomal RNA. This lack of sufficient ribosomal RNA is detrimental to the survival of DRG neurons.37 The progressive accumulation of DNA-platinum adducts in DRG neurons induces neurophysiological alterations and increases neuronal cell death, which ultimately manifests clinically as neuropathic pain.39
Platinum can also bind to mitochondrial DNA (mtDNA) and cause morphological impairments in mitochondrial function.37 Oxidative stress, closely associated with mitochondrial dysfunction, is a significant contributor to neurodegenerative diseases and nerve injuries, often accompanied by painful symptoms.40 Neurons are particularly vulnerable to oxidative stress because they contain high levels of unsaturated fatty acids and oxidation-sensitive proteins.41 Excessive production of mitochondrial ROS (mtROS) can trigger neuroinflammation by promoting the ectodomain of cardiolipin being translocated from the inner to the outer mitochondrial membrane. This provides an anchoring site for the nucleotide-binding oligomerization domain-like receptor pyrin domain-containing 3 (NLRP3) receptor and caspase-1 and activates the NLRP3 inflammasome.42 Abnormal activation of the NLRP3 inflammasome in neurons is a critical pathological mechanism underlying platinum-induced neuroinflammation. Due to the high content of oxidation-sensitive components, neurons are more susceptible to dysfunction and apoptosis under oxidative stress, ultimately leading to neuropathic pain (Figure 3).
Mechanisms of doxorubicin-induced neuropathic pain
Doxorubicin (DOX), the FDA-approved chemotherapeutic drug, is extensively utilized in clinical oncology for treating various malignancies such as breast cancer and sarcomas.43
DOX-induced neurotoxicity is closely linked to the overproduction of ROS. This occurs through NADPH and cytochrome P450 reductase-mediated one-electron reduction of DOX’s quinone moiety, forming a semiquinone free radical. This free radical interacts with oxygen (O2) to produce superoxide radical O2·−.44 The sustained generation of ROS leads to a cascade of oxidative stress, damaging DNA, proteins, and lipids. This damage triggers cellular dysfunction or death, contributing to the neurotoxic effects of DOX.45
DOX stimulates mitochondrial disruption and ROS production, which leads to cell membrane disruption and activation of apoptosis.46 This oxidative stress disrupts mitochondrial outer membrane permeability (MOMP), alters the Bax/Bcl-2 ratio, and contributes to the release of cytochrome c (Cyt C) from the mitochondria. This release activates apoptotic pathways, leading to impaired function of cognitively relevant brain regions.47,48 Studies show that DOX significantly increases apoptotic markers in the hippocampus, including cleaved caspase-3 and caspase-9 activity, enhanced Cyt C expression, elevated p53 levels, and reduced Bcl-2 expression,49,50 confirming the apoptotic mechanism responsible for DOX-induced neuronal cell death. This cascade culminates in the degeneration of neurons in cognition-related regions (e.g., the hippocampus) and ultimately results in neuropathic pain (Figure 4).
Therapeutic strategies for neuropathic cancer pain
Based on the complex pathogenesis of NCP, therapeutic exploration has expanded into diverse frontiers. The following sections stratify these interventions into molecular targets and pharmacological modulations and innovative emerging therapeutic strategies, with a comparative analysis of the latter presented in Table 1.ASO Nanotechnology Neuro-Tumor Interactions Endocannabinoid System Mechanisms Silencing the expression of Nav1.8 to halt nociceptive signal generation51 Encapsulating drugs into carriers to enable targeted delivery52 Blocking neuro-tumor signaling pathways28 Activating cannabinoid receptors, modulating ion channels, and inhibiting neuroinflammation and oxidative stress53,54,55 Advantages High specificity; low off-target effects56 Enhance bioavailability;
Reduce chemical degradation; low off-target effects57Pain relief; anti-tumor effects28 Broad-spectrum analgesic efficacy53 Challenges Rapid degradation58;
Poor membrane permeability59;
Off-target toxicity60In vivo interactions with blood components and tissues remain not fully understood6 Potential interference with physiological neural functions61 Scarcity of Clinical Efficacy Evidence53 Current
Clinical stagesThe majority are currently in Phase I/II trials60 A variety of nanomaterials have been applied in clinical use62 The majority are in clinical trials61 The clinical translation of ECS therapies remains in its early stages53
Molecular targets and pharmacological modulations
Transient receptor potential channel modulation
The regulation of TRPA1 and TRPV1 has been shown to be effective in a variety of preclinical pain models, including inflammatory pain and cancer pain.63 Clinically, 8% capsaicin patches (applied for 30–60 min every 3 months) are suggested as a second-line treatment for neuropathic pain.64 Capsaicin reduces pain by activating TRPV1 receptors, which become desensitized after repeated stimulation.16
Modulating the cyclic adenosine monophosphate/exchange protein directly activated by cyclic adenosine monophosphate pathway
Recent studies have demonstrated that EPAC1 isoforms facilitate the progression of multiple chronic pain conditions through the activation of specific downstream pathways. In a model of persistent postoperative pain, the EPAC1/PKC-betaII signaling cascade was found to modulate pain maintenance.65 Inhibition of EPAC1 and its downstream molecules effectively alleviated inflammatory pain in a bone cancer pain model,66 highlighting the importance of the pathway in chronic pain treatment.
At the molecular level, the cAMP activation of EPAC1 triggers its translocation to the plasma membrane, where it activates effector molecules, such as RAP1 and PKCε.4 Activated PKCε can enter the mitochondria and inhibit the respiratory activity of complex I, as well as reduce Na+-K+-ATPase activity, which ultimately impairs mitochondrial function.67 Blocking the translocation of EPAC1 to the plasma membrane effectively inhibits PKCε activation and its accumulation in the mitochondria, restoring mitochondrial oxidative phosphorylation and re-establishing ion homeostasis. This mechanism provides a theoretical basis for improving pain associated with mitochondrial dysfunction by regulating the cAMP/EPAC1 pathway.
Antioxidant therapies targeting NF-E2 related factor 2/kelch-like ech-associated protein 1 pathway
In physiological conditions, cytoplasmic Nrf2 is stabilized through its interaction with kelch-like ech-associated protein 1 (Keap1). When cells are exposed to oxidative stress, Nrf2-Keap1 complex dissociates, and Nrf2 translocates to the nucleus, where it binds to the antioxidant response element (ARE), triggering the transcription of antioxidant elements such as heme oxygenase-1 (H O -1) to enhance antioxidant defenses.68 Curcumin (Cur) exerts its protective effects by actively promoting this dissociation of Nrf2 from Keap1, allowing the activated Nrf2 to translocate to the nucleus.69
It has been demonstrated that Nrf2 undergoes polyubiquitination modification, which leads to its degradation by the proteasome, thereby limiting the activation of its downstream signaling. However, when cells are exposed to TNF-α, this cytokine inhibits the function of the antioxidant defense system by accelerating the degradation of Nrf2 through a significant increase in its polyubiquitination level.70 Cur inhibits the TNF-α-induced increase in Nrf2 polyubiquitination, while also prolonging the degradation cycle of Nrf2 protein to two times its basal state. This mechanism of maintaining Nrf2 protein activity by stabilizing its level provides a crucial molecular basis for activating the antioxidant defense system and the cytoprotective effects of Cur.70 In the pathogenesis and progression of NCP, the Nrf2/Keap1 pathway serves as a central regulator of intracellular antioxidant defenses, mitigating oxidative stress-induced neuronal and mitochondrial damage and thereby preventing the abnormal amplification of nociceptive signaling (Figure 5).
Innovative therapeutic approaches in neuropathic cancer pain
Antisense oligonucleotides technology in pain management and cancer therapy
ASO is a single-stranded DNA molecule consisting of 14–25 synthetic nucleotides that bind specifically to target mRNAs with low off-target effects.56 ASO technology has demonstrated multidimensional application potential in disease treatment and pain management.
The tetrodotoxin (TTX)-tolerant sodium channel subunit NaV1.8, a marker of damaged receptors, plays a critical role in pain signaling, with its expression level closely linked to the sensation of pain. Studies have demonstrated that ASO can effectively correct the abnormal distribution of sodium channels in sciatic nerve injury models by targeting and reducing the expression of NaV1.8 in DRG neurons, ultimately reversing neuropathic pain symptoms.51 Meanwhile, ASO technology has also made breakthroughs in cancer treatment. Researchers have innovatively developed an NQO1 enzyme-activated circular ASO system, which specifically activates through the NQO1 enzyme, highly expressed in the tumor microenvironment, thereby successfully establishing a tumor cell-specific gene silencing platform.71 Targeting glioma stem cell-associated lncRNA with antisense oligonucleotides significantly suppressed tumor cell proliferation and migration, showing promising clinical application potential.72 ASO technology has shown considerable promise in gene therapy due to its ability to target specific mRNA sequences and regulate gene expression precisely.
Nanotechnology in pain management and cancer therapy
Nanotechnology can enhance the water solubility of lipophilic compounds and promote the transmembrane transport of hydrophilic drugs. Additionally, by stabilizing drug structures and inhibiting aggregation, they effectively address key challenges such as low bioavailability, chemical degradation, and off-target effects.57 The innovative nanotechnology is a driving breakthrough in the clinical treatment of pain management.
Nanomaterials such as liposomes and poly(lactic-co-glycolic acid) (PLGA) have been approved by the US FDA for clinical use.52 For example, PEGylated liposomes have been shown to effectively encapsulate zoledronic acid (ZOL), penetrate the blood-brain barrier, and promote ZOL release. Animal studies have demonstrated that liposome-encapsulated hydromorphone can prolong analgesic effects with a single administration.52 Zinc oxide nanoparticles (nZnO) have been effective in antagonizing neuropathic pain and nociceptive hypersensitivity by targeting elevated zinc ion concentrations as a non-competitive inhibitor of NMDA receptors.73
Cur can enhance cellular antioxidant defenses by activating the Nrf2 pathway, but its clinical application is limited by poor solubility, a high degradation rate, and low bioavailability.74 Recent advancements in nanotechnology have created opportunities to improve Cur’s effectiveness in drug delivery. For example, in a study involving patients with bladder cancer undergoing chemotherapy, curcumin nanomicelles improved clinical response rates without significant adverse effects. Additionally, a study involving patients with breast cancer found that nano-curcumin reduced skin damage and discomfort caused by radiation. These findings highlight the advantages of nanotechnology in reducing the adverse effects of cancer therapies and enhancing the efficacy of Cur.75
Targeting neural-tumor interactions
Cancer neuroscience has recently emerged as a rapidly growing research field, focusing on how the nervous system regulates tumor initiation and progression. Studies suggest that key molecules mediating neural-tumor interactions, such as neurotransmitters and their associated signaling pathways, may represent promising therapeutic targets for cancer treatment.
Neurotrophic factors, particularly NGF, are involved in tumor progression through multiple mechanisms. Under low-glucose conditions, NGF secreted by cancer cells promotes the release of CGRP from nociceptive neurons, thereby driving tumor growth.61 NGF-dependent aberrant sprouting of nociceptive nerves has been observed in gastric cancer models,24 while in colorectal cancer, NGF enhances tumor proliferation via activation of the Trka receptor downstream PI3K-AKT pathway.76 These findings highlight the potential therapeutic value of targeting NGF and its receptors. The CGRP signaling pathway also exhibits therapeutic promise. In pancreatic cancer, nociceptive neurons are stimulated by CAFs through NGF secretion, resulting in increased CGRP release. Neuron-derived CGRP, in turn, suppresses IL-15 production from CAFs, leading to impaired NK cell function and fostering an immunosuppressive microenvironment. Notably, patients with increased CGRP+ nociceptive innervation experience more intense cancer-related pain.28 Furthermore, CGRP binds to the Calcrl/RAMP1 receptor, activating PI3K and CaMK pathways in gastric cancer cells to promote malignant progression.24 In oxaliplatin-induced peripheral neuropathy models, increased CGRP levels in the dorsal horn further underscore its role in NCP.77 Clinically, the CGRP receptor antagonist rimegepant—approved for migraine—demonstrated significant antitumor effects in a PDAC mouse model, reducing tumor burden and prolonging survival.28 In a randomized, double-blind, placebo-controlled trial, the study confirmed that oral rimegepant tablets are effective in the acute treatment of migraine, with a safety and tolerability profile comparable to that of a placebo.78 Current evidence suggests that targeting NGF and CGRP receptors may not only inhibit tumor growth but also mitigate cancer-related neuropathic pain, offering a therapeutic strategy.
Regulation of the endocannabinoid system in neuropathic cancer pain
The ECS, comprising cannabinoid receptors (CB1 and CB2), endogenous ligands (e.g., anandamide and 2-AG), and their metabolic enzymes, constitutes a pivotal regulatory network for pain and inflammation, representing a highly promising therapeutic target for NCP.53 Its analgesic and anti-inflammatory efficacy is mediated by multiple synergistic mechanisms, including receptor activation, modulation of ion channels, and suppression of neuroinflammation and oxidative stress.
First, CB1 receptors, abundant in the CNS, and CB2 receptors, predominantly expressed in peripheral immune tissues, serve as key mediators of analgesia.53 A systematic preclinical analysis demonstrated that agonists targeting either CB1 or CB2 receptors effectively attenuate nociceptive transmission, thereby alleviating neuropathic pain.53 In animal models of CIBP, the activation of both CB1 and CB2 receptors produced significant analgesic effects, and bioinformatic analyses revealed that CB1 and CB2 receptors are significantly enriched in signaling pathways associated with nociception and sensory perception, inflammatory responses, immune regulation, and cancer-related processes,54 highlighting the pivotal role of cannabinoid receptor activation in the treatment of NCP. Second, ECS inhibits pain signal transmission by modulating ion channel activity and neuronal excitability. Studies have shown that the endocannabinoid anandamide exerts analgesic and anti-inflammatory effects through CB1 receptor activation and regulation of ATP-sensitive potassium channels, thereby alleviating neuropathic pain.55 Mechanistically, CB1 receptor activation couples to Gi/o proteins, leading to the inhibition of adenylate cyclase activity, subsequent blockade of voltage-dependent Ca2+ channels, and opening of potassium channels that promote K+ efflux. These alterations in ionic flux induce neuronal membrane hyperpolarization, reduce neuronal excitability, and ultimately suppress neuropathic pain signaling.79 Finally, the ECS alleviates neuropathic pain through coordinated suppression of neuroinflammation and oxidative stress. In addition to similar electrophysiological effects, the activation of CB2 receptors promotes the release of anti-inflammatory cytokines, including interleukin-4 (IL-4), interleukin-10 (IL-10), and NGF, while downregulating the pro-inflammatory cytokine IL-1β, thereby attenuating neuroinflammation and alleviating neuropathic pain.79 In a chronic constriction injury (CCI) model, the administration of endocannabinoids not only significantly reduced pain-related behaviors but also exerted neuroprotective effects via antioxidant mechanisms. ECS activation markedly decreased the levels of key oxidative stress biomarkers, including lipid peroxides and nitrite compounds,55 suggesting that the ECS effectively scavenges reactive oxygen species generated within inflammatory microenvironments, restores redox homeostasis, and thereby restrains the pathological progression of NCP (Figure 6).
Future perspectives
Despite rapid progress in elucidating treatments for NCP, a significant translational gap remains between preclinical findings and effective clinical management. To advance this field, future research must address specific technical challenges and clinical hurdles associated with emerging therapies.
Firstly, ASO technology has demonstrated excellent targeting specificity in silencing pain-related genes such as Nav1.8. However, ASO are susceptible to rapid degradation by endogenous nucleases.58 Furthermore, their strong negative charge and poor membrane permeability result in low cellular uptake rates,59 and potential off-target toxicity remains a safety concern limiting their application.60 Therefore, future research should focus on two main directions: (1) conducting comprehensive long-term clinical safety assessments to verify in vivo safety.60 (2) combining personalized ASO design with lipid nanovesicle (LNV) delivery systems, which not only effectively protects ASO from degradation but also enables efficient intracellular delivery.60 This combination represents a frontier in precision oncology, offering a safer and more effective platform for gene therapy.
Additionally, nanotechnology has significantly improved the solubility and transmembrane bioavailability of lipophilic drugs such as Cur, but the in vivo biodistribution profiles of nanomaterials and their long-term interactions with blood, tissues, and the immune system remain to be fully elucidated.6 Currently, carrier stability remains a major bottleneck for clinical translation. For instance, conventional liposomes are sensitive to fluctuations in environmental pH and temperature, while high doses of cationic liposomes are associated with potential cytotoxicity risks.6 Future research should focus on: (1) conducting systematic and comprehensive toxicological evaluations; and (2) constructing intelligent, stimuli-responsive nanocarriers (e.g., pH-sensitive or enzyme-triggered). By leveraging the acidic or inflammatory characteristics of the TME, these carriers can facilitate precise, site-specific drug release, thereby maximizing the reduction of systemic side effects.
Targeting neuro-tumor interactions (such as blocking NGF or CGRP signaling) represents a therapeutic strategy with “dual-benefit” potential, holding the promise of simultaneously suppressing tumors and alleviating pain. However, results indicate that inhibiting these neurosecretory factors may interfere with normal physiological neural signaling, leading to adverse events.61 To overcome this challenge, future strategies should focus on utilizing next-generation nanomaterial technology to traverse the BBB and precisely deliver therapeutics to the TME. This strategy aims to achieve localized blockade of neural signals at the lesion site, thereby maximizing neuroprotection and reducing systemic side effects while maintaining efficacy.80 Given the high complexity and heterogeneity of interactions between nerves and tumors, it is essential to further dissect the specific functional differences of various nerve fiber types within specific tumor contexts. This will enable the development of more targeted and highly specific drugs.61
Moreover, targeting the ECS has demonstrated significant broad-spectrum analgesic potential in various preclinical models, ranging from rodent models of inflammatory and neuropathic pain to CIBP.53,54 Beyond its analgesic properties, cannabinoid receptor activation is implicated in the regulation of critical oncogenic processes, including cell proliferation, apoptosis, and angiogenesis, suggesting that the ECS may directly modulate tumor progression.81 Furthermore, endocannabinoids effectively alleviate cancer-associated symptoms, such as nausea, pain, and anorexia, with a favorable tolerability profile, and have shown marked synergistic effects when combined with conventional therapies such as chemotherapy and radiotherapy.81 Collectively, these multifaceted attributes underscore the robust potential of the ECS for clinical translation. However, current drug development remains hindered by a formidable translational gap. While a vast body of preclinical literature supports the hypothesis of cannabinoid-induced analgesia, confirmatory evidence of its efficacy in human pain patients remains scarce, and existing clinical data are often characterized by low to very low quality.53 This evidential deficit significantly constrains the clinical implementation of endocannabinoid-based therapies. To overcome this bottleneck, future research must prioritize the optimization of preclinical evaluation systems. Specifically, there is an urgent need to refine experimental animal models to enhance their translational predictive value. Next-generation models must evolve to capture the multidimensional features of clinical pathological states, with a particular emphasis on assessing spontaneous pain and affective comorbidities, such as anxiety, stress, and depression.53 Re-evaluating novel interventions within these complex models, which accurately reflect endocannabinoid tone, enzymatic activity, and receptor dynamics, will facilitate a more precise validation of therapeutic efficacy and ultimately drive the success of clinical translation.
Conclusion
The review effectively makes a clear differentiation between tumor and chemotherapy-induced neuropathic pain, as they involve distinct molecular pathways, laying a solid theoretical foundation for the development of therapeutic strategies. Building on this, the application of TRP channel blockers and the modulation of specific molecular targets have formed the cornerstone of current pharmacological treatments. Emerging technologies, particularly ASO, nanotechnology-based drug delivery systems, therapies targeting neuro-tumor interactions, and ECS, offer promising avenues to provide a theoretical foundation and potential intervention targets for precision cancer pain management. However, their widespread clinical adoption hinges on overcoming current technical limitations. Successfully resolving these bottlenecks to optimize the bioavailability and safety of these novel modalities will represent a transformative breakthrough, ultimately revolutionizing NCP management and significantly improving the quality of life for patients with cancer.
Acknowledgments
This work was supported by the Keynote Research Project of Ningbo City (2023Z171).
Declaration of interests
The authors declare no conflict of interest.
Declaration of generative AI and AI-assisted technologies in the writing process
Language editing was helped by ChatGPT. Photos are edited by Figdraw. After using this tool/service, the authors reviewed and edited the content as needed and take full responsibility for the content of the publication.