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OBM Neurobiology

(ISSN 2573-4407)

OBM Neurobiology is an international peer-reviewed Open Access journal published quarterly online by LIDSEN Publishing Inc. By design, the scope of OBM Neurobiology is broad, so as to reflect the multidisciplinary nature of the field of Neurobiology that interfaces biology with the fundamental and clinical neurosciences. As such, OBM Neurobiology embraces rigorous multidisciplinary investigations into the form and function of neurons and glia that make up the nervous system, either individually or in ensemble, in health or disease. OBM Neurobiology welcomes original contributions that employ a combination of molecular, cellular, systems and behavioral approaches to report novel neuroanatomical, neuropharmacological, neurophysiological and neurobehavioral findings related to the following aspects of the nervous system: Signal Transduction and Neurotransmission; Neural Circuits and Systems Neurobiology; Nervous System Development and Aging; Neurobiology of Nervous System Diseases (e.g., Developmental Brain Disorders; Neurodegenerative Disorders).

OBM Neurobiology publishes a variety of article types (Original Research, Review, Communication, Opinion, Comment, Conference Report, Technical Note, Book Review, etc.). Although the OBM Neurobiology Editorial Board encourages authors to be succinct, there is no restriction on the length of the papers. Authors should present their results in as much detail as possible, as reviewers are encouraged to emphasize scientific rigor and reproducibility.

Publication Speed (median values for papers published in 2024): Submission to First Decision: 7.6 weeks; Submission to Acceptance: 13.6 weeks; Acceptance to Publication: 6 days (1-2 days of FREE language polishing included)

Current Issue: 2025  Archive: 2024 2023 2022 2021 2020 2019 2018 2017
Open Access Review

Neurobiology of Cancer Pain: A Narrative Review

Giustino Varrassi 1,2 ORCID logo , Matteo Luigi Giuseppe Leoni 3,*, Giacomo Farì 4, Annalisa Caruso 5, Ameen Abdulhasan Al-Alwany 2, Marco Mercieri 3, Joseph V. Pergolizzi 6, Rocìo Guillen 7

  1. Fondazione Paolo Procacci, 00193 Rome, Italy

  2. College of Medicine, University of Bagdad, Bagdad, Iraq

  3. Department of Medical and Surgical Sciences and Translational Medicine, Sapienza University of Rome, 00189 Rome, Italy

  4. Department of Experimental Medicine (Di.Me.S.), University of Salento, Lecce, Italy

  5. Department of Surgery, ASST Lodi, Lodi, Italy

  6. NEMA Research Group, Neaples, FL, USA

  7. Pain Medicine, National Cancer Institute, Mexico City, Mexico

* Correspondence: Matteo Luigi Giuseppe Leoni

Academic Editor: Giuseppe Biagini

Special Issue: Pain and Neurobiology

Received: September 10, 2025 | Accepted: December 01, 2025 | Published: December 12, 2025

OBM Neurobiology 2025, Volume 9, Issue 4, doi:10.21926/obm.neurobiol.2504315

Recommended citation: Varrassi G, Leoni MLG, Farì G, Caruso A, Al-Alwany AA, Mercieri M, Pergolizzi JV, Guillen R. Neurobiology of Cancer Pain: A Narrative Review. OBM Neurobiology 2025; 9(4): 315; doi:10.21926/obm.neurobiol.2504315.

© 2025 by the authors. This is an open access article distributed under the conditions of the Creative Commons by Attribution License, which permits unrestricted use, distribution, and reproduction in any medium or format, provided the original work is correctly cited.

Abstract

Chronic cancer pain results from the complex interaction of nociceptive, neuropathic, and neuroimmune mechanisms, which vary according to tumor type, location, stage, and treatment history. Recent advances in cancer neuroscience have reframed pain as a dynamic manifestation of reciprocal tumor–nerve–immune interactions, rather than a mere consequence of tissue damage. In this model, malignant, stromal, and immune cells remodel nociceptive circuits at peripheral and central levels. This narrative review, conducted in accordance with SANRA criteria, synthesizes current mechanistic insights into the neurobiology of cancer pain. At the peripheral level, tumor-derived mediators such as prostaglandins, cytokines, chemokines, glutamate, and endothelin-1 drive nociceptor sensitization via G-protein–coupled and tyrosine kinase pathways. In bone metastases, osteoclast-mediated resorption generates an acidic microenvironment that activates acid-sensing ion channels and transient receptor potential (TRP) channels, linking skeletal destruction with movement-evoked pain. Pathological nerve remodeling and perineural invasion further contribute to neuropathic components and adverse oncological outcomes. Treatment-induced syndromes, notably chemotherapy-induced peripheral neuropathy, result from axonal injury, mitochondrial dysfunction, and neuroinflammation. At the central level, persistent afferent input induces glial activation and chemokine signaling, amplifying synaptic transmission and promoting central sensitization. Emerging evidence also highlights epigenetic regulation, noncoding RNAs, and tumor–immune–neural crosstalk as potential therapeutic targets. Collectively, these findings position cancer pain as a disorder of aberrant tumor–nerve–immune signaling. Effective management requires precision strategies integrating mechanism-guided pharmacology, neuromodulation, and supportive care. This review emphasizes the need for translational research to bridge mechanistic discoveries with personalized, multimodal interventions in oncology.

Keywords

Cancer pain; tumor-nerve interactions; chemotherapy-induced peripheral neuropathy; bone metastases; neuroinflammation

1. Introduction

Cancer pain affects approximately 55% of patients undergoing active treatment and up to 66% of those with advanced disease, representing one of the most feared complications of malignancy [1]. This pain experience encompasses diverse phenotypes ranging from acute nociceptive pain at tumor sites to chronic neuropathic syndromes following treatment. It significantly impacts quality of life, functional capacity, and survival outcomes [2,3]. Despite advances in oncology and pain medicine, inadequate pain control persists in 30-40% of cancer patients, highlighting critical gaps in our understanding of underlying mechanisms and therapeutic targeting [4,5].

Cancer pain is a heterogeneous, multidimensional experience driven by converging nociceptive, neuropathic, and neuroimmune mechanisms that vary by tumor type, anatomical site, disease stage, and prior anticancer treatments [6]. Recent advances in cancer neuroscience have reframed pain as a dynamic manifestation of reciprocal tumor–nerve–immune interactions, rather than a mere consequence of tissue damage. In this framework, malignant, stromal, and immune cells remodel peripheral and central nociceptive circuits [7,8]. Appreciating these interactions clarifies why many patients manifest mixed pain phenotypes and why mechanism-guided therapy is needed beyond simple escalation of opioids [9].

Fundamental insights into cancer pain neurobiology come from relevant studies demonstrating how tumors provoke nociceptive sensitization via secretion of algogenic mediators and by disrupting nerve function, a view grounded in both animal models and clinical observations [10,11]. These tumor-mediated mechanisms are exemplified in bone metastases, where tumor-induced osteoclastic resorption generates an acidic microenvironment that activates acid-sensing receptors on peripheral nociceptors, thereby directly coupling structural bone destruction with severe, often movement-related pain [12]. In contrast to tumor-driven pain mechanisms, chemotherapy-induced peripheral neuropathy (CIPN) represents a common iatrogenic pain phenomenon resulting from cumulative damage to dorsal root ganglia (DRG) and peripheral axons. This damage occurs through multiple pathways, including microtubule disruption, mitochondrial dysfunction, ion channel dysregulation, and neuroinflammation [13]. Of particular clinical significance, oral CIPN manifestations are especially distressing and occur with notable frequency [14].

The neurobiology of cancer pain involves unique features not typically observed in other chronic pain conditions. Tumors secrete neurotrophic factors, cytokines, chemokines, and metabolites such as adenosine triphosphate (ATP), glutamate, and protons, which directly excite or sensitize peripheral nociceptors [10,12]. Bone metastases generate a distinctive acidic microenvironment through osteoclast-mediated resorption, which activates acid-sensing ion channels (ASIC) and transient receptor potential (TRP) channels on peripheral sensory neurons, thereby directly coupling skeletal destruction with severe, often movement-related pain [14]. Beyond peripheral mechanisms, cancers promote pathological nerve sprouting and perineural invasion (PNI), which contribute to severe neuropathic components of pain and have been linked to disease progression [15].

At the central level, spinal microglia and astrocytes become chronically activated by persistent afferent input. They release proinflammatory cytokines and chemokines that amplify synaptic transmission and diminish inhibitory control, ultimately driving central sensitization [16,17,18]. In parallel, supraspinal circuits involved in affect, cognition, and descending modulation undergo maladaptive plasticity, contributing to the emotional and cognitive burden of cancer pain [19]. Importantly, as already mentioned, pain in oncology is not only tumor-driven but also treatment-induced. Chemotherapy, radiotherapy, and surgery can damage peripheral and central neural structures, producing long-lasting neuropathic syndromes such as CIPN, which substantially affect survivorship [20,21]. Collectively, these insights highlight cancer pain as a disorder of aberrant tumor–nerve–immune crosstalk, where effective management requires integrating pathophysiological understanding into personalized, multimodal strategies.

The purpose of this narrative review is to synthesize and critically appraise emerging insights into the neurobiology of cancer pain, highlighting how tumor–nerve–immune interactions contribute to its complex and heterogeneous clinical presentation. By integrating mechanistic evidence across peripheral, central, and treatment-induced pathways, this work aims to support the development of more precise, mechanism-guided strategies for effective and personalized pain management in oncology.

2. Methods

This research was designed as a narrative review, developed in accordance with the Scale for the Assessment of Narrative Review Articles (SANRA), which ensures methodological rigor, transparency, and coherence in narrative synthesis [22].

2.1 Literature Search Strategy

A comprehensive, non-systematic literature review was conducted between June and August 2025. Major electronic databases, including PubMed/MEDLINE, Scopus, and Web of Science, were queried using a combination of controlled vocabulary and free-text terms. Search strings included: “cancer pain”, “neurobiology”, “tumor–nerve interactions”, “neuroimmune mechanisms”, “bone metastasis pain”, “perineural invasion”, and “chemotherapy-induced peripheral neuropathy”. Boolean operators and filters were applied to refine results. Only articles published in peer-reviewed journals, in English, and between 2000 and 2025 were considered to ensure both foundational knowledge and the inclusion of contemporary developments in cancer neuroscience.

2.2 Eligibility Criteria

Included studies encompassed original experimental research (both preclinical and clinical), systematic and narrative reviews, and clinical guidelines relevant to the neurobiology of cancer pain. Priority was given to publications addressing mechanistic pathways at peripheral, central, or treatment-related levels. Exclusion criteria were articles not directly related to cancer pain mechanisms (e.g., general oncology without a pain component), case reports with insufficient mechanistic focus, and non-peer-reviewed sources.

2.3 Data Extraction and Synthesis

Relevant data from eligible studies were extracted narratively, focusing on molecular mediators, cellular interactions, and neuroimmune crosstalk underlying cancer pain. Evidence was organized across major domains: peripheral mechanisms, central sensitization, tumor–nerve–immune crosstalk, translational implications, special context, and emerging directions. Reference lists of included articles were also screened for additional relevant sources. No quantitative synthesis (meta-analysis) was attempted, as this work aimed to provide a conceptual integration rather than statistical aggregation.

2.4 Quality Assurance

To maintain methodological soundness, the selection of literature and the synthesis process were independently cross-checked against SANRA recommendations. Emphasis was placed on scientific reasoning, critical analysis, and balanced reporting, while avoiding selective citation or overinterpretation. Table 1 illustrates the criteria used.

Table 1 Compliance of the present review with the SANRA domains.

3. Results

3.1 Peripheral Mechanisms

3.1.1 Tumor- and Stroma-Derived Mediators

The tumor microenvironment is a complex milieu of algogenic factors that orchestrate peripheral sensitization through multiple convergent pathways. Prostaglandins, particularly prostaglandin E2 (PGE2) generated via cyclooxygenase-2 (COX-2) upregulation in tumor and stromal cells, serve as primary mediators of inflammatory pain. They sensitize nociceptors through EP receptor activation and subsequent protein kinase A (PKA) and protein kinase C (PKC) signaling cascades. This prostanoid-driven sensitization works synergistically with a constellation of inflammatory cytokines, including interleukin-1β (IL-1β), tumor necrosis factor-α (TNF-α), and interleukin-6 (IL-6). These cytokines not only directly activate their respective receptors on sensory neurons but also induce the release of secondary mediators from immune and glial cells. The chemokine network, particularly C-C motif chemokine ligand 2 (CCL2) and its receptor CCR2, further amplifies this sensitization by recruiting inflammatory cells. Additionally, CCL2/CCR2 signaling directly modulates neuronal excitability by transactivating TRP channels [23,24]. In oral and melanoma models, endothelin-1 (ET-1) acting at endothelin A (ETA) receptors emerges as a particularly potent peripheral algogen, with ETA antagonism producing morphine-scale antinociception in vivo [25]. Additionally, tumor glutamate export through the cystine/glutamate antiporter xCT (solute carrier family 7 member 11, SLC7A11) increases extracellular glutamate in tumor beds, including bone. This activates peripheral receptors and contributes to ongoing pain. Inhibiting xCT with sulfasalazine has been shown to attenuate pain behaviors in preclinical bone metastasis models [26].

3.1.2 Ion Channels and Nociceptor Sensitization

A hallmark of cancer pain is the coordinated upregulation of activity in TRP, purinergic, and acid-sensing channels, which collectively transform standard sensory processing into pathological hypersensitivity [27]. TRPV1 and transient receptor potential ankyrin 1 (TRPA1) channels are consistently implicated across soft-tissue and bone cancer models. Their enhanced expression and function contribute to both thermal hyperalgesia and mechanical allodynia [28]. Pharmacological blockade or defunctionalization of these channels reduces hyperalgesia in animal models, and clinical translation of TRPV1-targeting strategies, particularly resiniferatoxin, is currently underway with promising early results [29].

The purinergic system, specifically P2X3 and P2X2/3 receptors, mediates ATP-driven signaling from the tumor microenvironment and bone matrix. These receptors respond to the high concentrations of extracellular ATP released during cellular stress, tissue damage, and bone resorption. Selective antagonism or receptor silencing reduces cancer-induced bone pain (CIBP) in preclinical models, suggesting therapeutic potential [30,31]. Furthermore, tumor- or osteoclast-generated acidosis activates ASIC3 and TRPV1 on bone-innervating afferents, creating a direct mechanistic link between osteolysis and the spontaneous and movement-evoked pain that characterizes skeletal metastases [32,33,34].

3.1.3 Nerve Remodeling, Perineural Invasion, and Neurotropism

Cancers demonstrate a remarkable capacity to foster PNI and pathologic nerve sprouting, including both sensory and sympathetic fibers, driven in part by nerve growth factor (NGF) and other neurotrophic cues [35]. PNI is particularly prevalent in pancreatic and head-and-neck cancers, where it correlates with severe neuropathic pain and portends adverse oncological outcomes. Mechanistically, cancer–nerve crosstalk involves complex signaling cascades, including the hepatocyte growth factor/c-MET → mTOR → NGF pathway, which promotes tumor infiltration of nerve sheaths while simultaneously enhancing nociceptor sensitivity [36,37]. These described peripheral mechanisms converge to create a self-perpetuating cycle of sensitization. Figure 1 illustrates how tumor- and stroma-derived mediators activate ion channels and sensitize primary afferents, how inflammatory signaling lowers nociceptor thresholds, and how PNI driven by neurotrophic factors contributes to neuropathic pain. Together, these processes generate the complex pain phenotype characteristic of cancer.

Click to view original image

Figure 1 Peripheral mechanisms of cancer pain. Tumor- and stroma-derived mediators such as prostaglandins, cytokines (IL-1β, TNF-α, IL-6), chemokines (CCL2), endothelin-1 (ET-1), and glutamate lower nociceptor thresholds and enhance sodium current density via GPCR and NGF–TrkA pathways. Up-regulated activity in TRP, purinergic, and ASIC channels drives persistent background pain, movement-evoked flares, hyperalgesia, and allodynia. In parallel, inflammatory signaling contributes to peripheral sensitization, while nerve remodeling and perineural invasion, mediated in part by NGF and HGF/c-MET → mTOR signaling, promote neuropathic pain and tumor infiltration of nerve sheaths.

3.1.4 Bone Cancer Pain: A Distinct Microenvironment

Bone represents the most common site of metastatic disease, with skeletal involvement occurring in up to 70% of patients with advanced breast and prostate cancers. The pathophysiology of CIBP involves a distinctive 'vicious cycle' wherein tumor cells stimulate osteoblasts to produce receptor activator of nuclear factor kappa-B ligand (RANKL). RANKL then binds to RANK receptors on osteoclast precursors, promoting their differentiation and activation. This enhanced osteoclastic activity not only causes structural bone destruction but also generates a unique acidic microenvironment (pH 4.0-5.0) by releasing protons during mineral resorption. This acidification, combined with the liberation of sequestered growth factors from the bone matrix, includes transforming growth factor-β (TGF-β) and insulin-like growth factor-1 (IGF-1). Together, these conditions both promote tumor growth and intensify nociception [12,38]. The acidic milieu directly activates ASIC3 and TRPV1 on bone-innervating sensory fibers. Simultaneously, ATP released during osteolysis engages P2X3 and P2X2/3 purinergic receptors. Collectively, these mechanisms drive both spontaneous pain and the severe movement-evoked pain characteristic of skeletal metastases. Additionally, this microenvironment promotes exuberant NGF-dependent sprouting of nociceptors, further amplifying pain signaling [33,39]. Studies have synthesized robust preclinical evidence, and the translational signal that targeting osteoclasts with bisphosphonates or denosumab reduces both skeletal events and pain intensity [33,40,41]. Figure 2 depicts this vicious cycle of tumor–bone interaction and therapeutic strategies targeting osteoclast activity.

Click to view original image

Figure 2 Vicious cycle of tumor–bone interaction in metastatic bone pain. Under normal bone homeostasis, bone formation by osteoblasts (OBs) and bone resorption by osteoclasts (OCs) remain balanced. In the metastatic setting, cancer cells induce OBs to secrete RANKL, which binds to RANK on OCs, driving their proliferation and activity. Activated OCs increase bone resorption, acidify the microenvironment, and release pro-tumorigenic growth factors (e.g., IGF-1, TGF-β), further fueling tumor progression. These processes enhance afferent sensitization via ASIC3, TRPV1, and P2X3, producing persistent and movement-evoked pain. Therapeutically, bisphosphonates (high affinity for OCs, inducing apoptosis) and denosumab (anti-RANKL monoclonal antibody) disrupt this cycle, reducing skeletal events and cancer pain.

3.1.5 Treatment-Induced Neurotoxicity and Pain

CIPN, common with platinum compounds, taxanes, vinca alkaloids, and bortezomib, results from a complex interplay of pathological mechanisms that converge to produce sensory dysfunction and pain. The underlying pathophysiology involves combined axonal transport failure, mitochondrial dysfunction, DNA adduct formation, ion channel remodeling, and neuroinflammation within DRG and peripheral nerves [42]. Although mechanistic details differ by agent—microtubule stabilization with taxanes, DNA crosslinking with platinums, proteasome inhibition with bortezomib—the convergent phenotype is consistent. It manifests as distal sensory neuropathy characterized by allodynia, burning pain, and numbness in a stocking-glove distribution [43]. Despite extensive research into preventive strategies, duloxetine remains the only guideline-supported analgesic for painful CIPN, highlighting the urgent need for mechanism-based therapeutic development [42,44].

3.1.6 Neuroinflammation in Cancer Pain

Neuroinflammation, characterized by activation of glial cells (microglia and astrocytes) and release of proinflammatory mediators within the nervous system, plays a pivotal role in the transition from acute to chronic cancer pain [17]. Unlike peripheral inflammation, neuroinflammation involves bidirectional communication between neurons and non-neuronal cells that fundamentally alters pain processing [17,45]. In cancer pain, neuroinflammation manifests at multiple anatomical levels: peripherally through tumor-associated immune cell infiltration and cytokine release (IL-1β, TNF-α, IL-6), within dorsal root ganglia via satellite glial cell activation, and centrally through spinal microglial and astrocytic responses to persistent nociceptive input [45]. Activated glia undergo morphological transformation, proliferate, and release neuromodulatory substances, including chemokines (CCL2, CX3CL1), brain-derived neurotrophic factor (BDNF), and ATP, which amplify synaptic transmission and reduce inhibitory tone [24,46]. This sustained neuroimmune activation creates a self-perpetuating environment that drives the neuroplastic changes underlying central sensitization.

3.2 Central Sensitization

3.2.1 Spinal Neuroinflammation and Disinhibition

Central sensitization in cancer pain emerges through coordinated glial-neuronal interactions that fundamentally alter spinal nociceptive processing. Persistent nociceptive input from tumor sites or treatment-induced injury triggers phenotypic changes in spinal microglia. These changes are characterized by morphological transformation from ramified to amoeboid forms and upregulation of purinergic P2X4 and P2X7 receptors. These activated microglia release brain-derived neurotrophic factor (BDNF), which disrupts chloride homeostasis in dorsal horn neurons by downregulating the potassium-chloride cotransporter KCC2. This converts gamma-aminobutyric acid (GABA) signaling from inhibitory to excitatory [47].

Concurrently, astrocytic activation, mediated through connexin-43 gap junctions and hemichannels, facilitates the release of glutamate, D-serine, and ATP, which amplify excitatory synaptic transmission while compromising inhibitory control. The chemokine signaling axis plays a crucial orchestrating role in this process, with fractalkine (CX3CL1) released from primary afferents binding to microglial CX3CR1 receptors, and CCL2-CCR2 interactions promoting sustained glial activation. Cancer-related models have demonstrated hippocampal and spinal cord activation of p38 mitogen-activated protein kinase (MAPK) in microglia, increased glial cytokines, and enhanced chemokine signaling. These changes potentiate synaptic transmission and weaken inhibitory control—canonical features of central sensitization that have been directly implicated in CIBP [48,49]. This creates a self-perpetuating cycle of central sensitization that underlies the transition from acute to chronic cancer pain.

3.2.2 Descending Modulation and Network-Level Changes

Functional alterations in descending inhibitory and excitatory controls, along with reorganization of cortical–subcortical circuits including limbic regions, contribute significantly to the affective–cognitive burden of cancer pain. These changes also influence opioid responsiveness [50,51]. While direct cancer-specific neuroimaging evidence remains limited, convergent findings from broader neuropathic pain literature and emerging neuromodulation studies suggest necessary supraspinal adaptations. These changes affect periaqueductal gray-rostral ventromedial medulla pathways, which generally usually modulate spinal nociceptive transmission, and may explain variability in response to interventions such as spinal cord stimulation (SCS) [52].

3.2.3 Tumor–Nerve–Immune Crosstalk

The tumor microenvironment (TME) represents the complex cellular and acellular ecosystem surrounding malignant cells, comprising stromal cells (fibroblasts, immune cells, endothelial cells), infiltrating neurons, extracellular matrix, and a milieu of secreted mediators including growth factors, cytokines, and chemokines [53]. This dynamic microenvironment serves as the principal anatomical site where tumor-nerve-immune crosstalk occurs, driving both cancer progression and pain [54]. The recognition of bidirectional signaling between nociceptors, immune cells, and tumor cells has fundamentally reshaped our understanding of cancer pain as an active participant in disease progression rather than merely a symptom. Nociceptors can shape tumor progression and immune infiltration in the microenvironment through the release of neuropeptides such as substance P and calcitonin gene-related peptide (CGRP). These neuropeptides modulate immune cell function and tumor cell behavior. Conversely, tumor-associated immune cells, including tumor-associated macrophages and myeloid-derived suppressor cells, release mediators that sensitize afferents, including IL-6, IL-1β, and CCL2 [27]. Recent publications even suggest that nociceptor-dependent mechanisms regulate myeloid-derived suppressor cells, supporting an integrated model in which analgesic strategies may modify disease biology [8].

3.3 Translational Implications

3.3.1 Mechanism-Guided Pharmacology

The translation of mechanistic insights into clinical practice has yielded several targeted approaches with demonstrated efficacy. In the bone microenvironment, anti-resorptive agents represent the most mature therapeutic strategy. Bisphosphonates and denosumab reduce skeletal-related events and improve pain control, with denosumab showing superiority to zoledronic acid in randomized trials for delaying skeletal events. In practice, both agents are used with appropriate dental and renal precautions. Radiotherapy, delivered as a single 8-Gy fraction or in short fractionated courses, remains highly effective for painful bone metastases, providing pain relief in approximately 60-70% of patients [41,55].

For peripheral sensitization, several promising targets have emerged. Endothelin axis antagonism is a rational strategy in tumors with high ET-1 expression, with preclinical studies demonstrating antinociception comparable to that of high-dose morphine [25]. TRP channel modulation, particularly defunctionalization of TRPV1-expressing afferents with resiniferatoxin, has progressed from companion-dog bone cancer studies to first-in-human trials. Initial phase-I data show clinically meaningful reductions in pain and opioid use with acceptable safety profiles in advanced cancer patients [56,57]. Purinergic signaling blockade with P2X3/P2X2/3 antagonists reduces CIBP behaviors in preclinical models, with clinical translation ongoing for pain indications in other conditions that may extend to cancer [32]. Central neuroinflammation presents attractive but challenging therapeutic targets. Chemokine signaling pathways (CX3CL1/CX3CR1; CCL2/CCR2) and microglial p38 MAPK have strong preclinical support in neuropathic and bone cancer pain models. However, the development of clinical inhibitors with adequate central nervous system penetration and acceptable safety profiles remains a significant translational gap [49].

3.3.2 Clinical Translation of Targeted Therapies

Recent years have witnessed significant progress in translating mechanistic insights into targeted therapies for cancer pain at the clinical stage. Several novel agents targeting specific molecular pathways are currently under investigation or have recently entered clinical practice.

Sodium Channel Modulators: Selective Nav1.7 and Nav1.8 inhibitors represent a promising class of peripherally-restricted analgesics. Nav1.8, predominantly expressed in nociceptors and upregulated in cancer pain states, has emerged as an attractive target. VX-548 (suzetrigine), a highly selective Nav1.8 inhibitor, has demonstrated encouraging efficacy in phase 2 trials for acute pain and is advancing toward phase 3 studies, with potential extension to cancer pain populations [58]. Unlike non-selective sodium channel blockers, these agents offer the advantage of reduced central nervous system side effects while maintaining analgesic efficacy.

TRPV1-Targeted Approaches: Resiniferatoxin (RTX), a highly potent capsaicin analogue, exhibits distinctive pharmacological properties [51]. It provides a wide therapeutic range, enabling complete desensitization of nociceptive pathways and neurogenic inflammation while maintaining an acceptable safety profile. When administered intravesically, RTX has been shown to restore bladder control in some patients with idiopathic or neurogenic detrusor overactivity. Acting as a “molecular scalpel,” RTX can selectively ablate pain-sensing neurons to produce long-lasting analgesia, a strategy currently being explored for cancer-related pain via intrathecal or epidural delivery [51]. Similar precision-targeted applications could extend to postoperative or burn-associated pain.

Anti-NGF Monoclonal Antibodies: Tanezumab and fasinumab, humanized monoclonal antibodies against NGF, have demonstrated robust analgesic efficacy in osteoarthritis and chronic low back pain trials [59]. Their application in cancer pain, particularly bone metastases, where NGF-driven sensitization is prominent, represents a rational extension. However, concerns regarding accelerated joint destruction in some patients have necessitated careful patient selection and monitoring protocols. Current investigations focus on identifying optimal dosing regimens and patient populations who may benefit while minimizing skeletal adverse events [60]. The dual mechanism of action—reducing both pain signaling and potentially limiting perineural invasion—positions anti-NGF therapies as disease-modifying agents rather than purely symptomatic treatments.

Chemokine Pathway Inhibitors: Maraviroc, a CCR5 antagonist approved for HIV treatment, has shown preclinical efficacy in neuropathic pain models and is being repurposed for investigation in painful chemotherapy-induced neuropathy [61]. Similarly, agents targeting the CCL2/CCR2 axis are in early-phase development and have the potential to address both peripheral sensitization and central neuroinflammation. The challenge remains achieving adequate CNS penetration while maintaining acceptable safety profiles.

Purinergic Receptor Antagonists: Gefapixant, a P2X3 receptor antagonist, has completed phase 3 trials for chronic cough [62] and demonstrated proof-of-concept efficacy in diabetic neuropathy [63]. Extension to cancer pain, particularly bone cancer pain, where ATP signaling is prominent, represents a logical translational pathway. The dose-limiting taste disturbance (dysgeusia) observed with gefapixant has prompted the development of next-generation P2X3 antagonists with improved therapeutic windows [64,65].

Table 2 summarizes the current landscape of mechanism-based pharmacologic interventions in cancer pain, including their molecular targets, stage of development, and key clinical considerations.

Table 2 Emerging and established therapies for cancer-related pain.

3.3.3 Neuromodulation and Interventional Approaches

For carefully selected patients with refractory mixed pain phenotypes, neuromodulation techniques offer critical therapeutic options. SCS may reduce pain intensity and opioid requirements in patients with predominant neuropathic components, with mechanistic advances pointing to both spinal gate control and supraspinal descending modulation effects [66,67]. Intrathecal drug delivery systems enable targeted delivery of opioids, local anesthetics, and adjuvant medications directly to spinal receptors, minimizing systemic side effects while maximizing analgesic efficacy. Sympathetic and celiac plexus blocks remain beneficial interventions for visceral cancer pain syndromes, particularly in pancreatic and upper gastrointestinal malignancies [68].

3.3.4 Clinical Translation and Precision Medicine Approaches

The heterogeneity of cancer pain mechanisms necessitates personalized assessment strategies that move beyond unidimensional pain scales. Quantitative sensory testing (QST) protocols, adapted from neuropathic pain assessment, can identify specific sensory phenotypes that predict treatment response [69]. For instance, patients exhibiting mechanical hyperalgesia and preserved thermal detection may respond preferentially to gabapentinoids. In contrast, those with profound thermal hypoesthesia and paradoxical heat sensations may benefit from sodium channel blockers [70]. Biomarker development, including circulating tumor DNA analysis for neural invasion markers and cerebrospinal fluid proteomics for central sensitization signatures, promises to enable mechanism-based patient stratification. Integration of these precision medicine approaches with traditional pain assessment tools could optimize therapeutic selection and improve outcomes in this challenging population [71].

3.4 Special Contexts

3.4.1 Pancreatic and Head-and-Neck Cancers

These malignancies present unique challenges due to their propensity for neural involvement. Severe neuropathic pain in these cancers often reflects dense PNI and neural remodeling, with up to 100% of pancreatic cancers demonstrating some degree of neural invasion at autopsy [72,73]. The HGF/c-MET → mTOR → NGF axis has been specifically implicated in promoting PNI and sensitization in these tumors. Strategies that disrupt this signaling loop may achieve dual analgesic and antitumor benefits, representing a promising area for targeted therapy development [37].

3.4.2 Chemotherapy-Induced Peripheral Neuropathy

The mechanistic heterogeneity of CIPN argues for agent-specific prevention and treatment approaches rather than a one-size-fits-all strategy. For platinum-based CIPN, mitochondrial stabilizers and antioxidants show promise, while microtubule-targeted interventions may be more appropriate for taxane-induced neuropathy [74,75]. Exercise programs and behavioral interventions demonstrate supportive evidence in mitigating symptom burden and improving functional outcomes, though high-quality disease-modifying therapies remain elusive [76]. The development of neuroprotective strategies that do not compromise antitumor efficacy represents a critical unmet need.

3.4.3 Emerging Directions

Recent advances point toward novel avenues in the mechanistic understanding and treatment of cancer pain. Epigenetic modifications and noncoding RNAs, particularly microRNAs, have emerged as key regulators of neuronal excitability and neuroinflammatory cascades [77]. Preclinical models of bone cancer pain demonstrate that histone acetylation and DNA methylation contribute to persistent nociceptor sensitization, while dysregulated miRNA expression modulates cytokine release and glial activation. For example, miR-199a-3p has been shown to suppress neuroinflammation by directly targeting MyD88 in mouse models of bone cancer pain, suggesting new epigenetic targets for intervention [12]. In parallel, efforts to refine clinical phenotyping by integrating QST, inflammatory biomarkers, and functional neuroimaging hold promise for distinguishing predominant pain mechanisms. This approach can identify whether nociceptive, neuropathic, or mixed drivers predominate, thereby informing mechanism-based therapies [78]. Advanced imaging techniques, such as functional magnetic resonance imaging (fMRI) and positron emission tomography (PET) using emerging ligands targeting glial activation, hold promise for future real-time assessment of central sensitization and treatment response. However, clinical validation in cancer pain is still lacking. Finally, the recognition of a dynamic tumor–nerve–immune triad highlights chemokine signaling pathways such as CCL2/CCR2 and CX3CL1/CX3CR1 as potential dual-action targets. These pathways may both attenuate nociceptor sensitization and favorably remodel the tumor microenvironment, offering an attractive strategy for translational research that bridges pain management with cancer therapeutics [79,80].

4. Discussion

The present narrative synthesis highlights the remarkable complexity of cancer pain, in which multiple peripheral and central mechanisms converge to shape a multidimensional clinical phenotype. The evidence reviewed underscores that tumor- and stroma-derived mediators, including prostaglandins, endothelins, cytokines, chemokines, and glutamate, serve as potent drivers of peripheral nociceptor sensitization [81]. These mediators not only lower neuronal thresholds but also promote aberrant ion channel activity, thereby sustaining spontaneous and evoked pain. Importantly, advances in experimental oncology suggest that interfering with these signaling cascades may yield analgesic benefits without reliance solely on opioids. Examples include ETA receptor antagonism or xCT-mediated glutamate release blockade [82].

The translational implications of these mechanistic insights extend beyond symptom management to potentially influence cancer progression itself. Emerging evidence suggests that adequate pain control may modify tumor biology through interruption of neural-tumor crosstalk. Studies show reduced tumor growth and metastasis following targeted denervation or nociceptor ablation [83]. This bidirectional relationship challenges the traditional view of pain as merely a symptom and positions it as an active participant in cancer pathophysiology. The therapeutic convergence of analgesic and antineoplastic effects, exemplified by anti-NGF antibodies that both reduce pain and inhibit PNI, represents a paradigm shift toward integrated cancer care. This is demonstrated by anti-NGF antibodies that both reduce pain and inhibit PNI, simultaneously addressing symptom burden and disease modification [84].

Ion channel dysregulation emerges as a particularly promising therapeutic target [85]. TRPV1 and TRPA1, along with P2X3 and ASIC3 receptors, link the tumor microenvironment to peripheral hyperexcitability, explaining both the background and movement-evoked components of CIBP. Translational studies with resiniferatoxin and P2X3 antagonists highlight the feasibility of moving from bench to bedside, although challenges remain in balancing efficacy with safety profiles and managing potential off-target effects [56,86].

The recognition of pathological nerve remodeling and PNI has deepened the understanding of neuropathic elements in cancer pain. PNI, common in pancreatic and head-and-neck cancers, is not only a source of severe pain but also a marker of aggressive disease biology and poor prognosis. Pathways such as HGF/c-MET–driven NGF upregulation suggest that interventions disrupting tumor–nerve crosstalk could achieve dual antitumor and analgesic effects. This represents a paradigm shift in supportive oncology that merges symptom control with disease modification [79,87].

Equally significant are central mechanisms, where glial activation and chemokine signaling sustain spinal hyperexcitability and diminish inhibitory tone. These processes resemble established neuropathic pain states but may be amplified by the unique tumor milieu and the systemic effects of cancer. While no CNS-penetrant inhibitors specifically targeting these pathways are yet approved for clinical use, ongoing preclinical studies strengthen the rationale for targeting glial–neuronal interactions as a therapeutic strategy [88,89].

From a translational perspective, therapies that modify the bone microenvironment remain the most mature and clinically validated approach. Anti-resorptives and radiotherapy are established treatments that reduce skeletal events and alleviate pain [90]. However, the persistence of CIPN despite various preventive strategies emphasizes the urgent need for disease-modifying interventions tailored to drug-specific neurotoxic mechanisms. The challenge lies in developing neuroprotective strategies that preserve antitumor efficacy while preventing or reversing neural damage [20,91]. Looking forward, integration of epigenetic and biomarker research with refined phenotyping approaches could enable patients to be grouped by predominant pain mechanisms, enabling truly personalized pain management strategies. This precision medicine approach may allow therapies not only to relieve suffering but also influence tumor-immune dynamics, potentially improving both quality of life and oncological outcomes. Ultimately, bridging mechanistic discoveries with precision interventions represents the central challenge and opportunity of contemporary cancer pain research.

4.1 Limitations

This narrative review is limited by its non-systematic methodology, which may introduce selection bias and restrict comprehensiveness. Although adherence to SANRA guidelines ensured transparency and rigor, the absence of a quantitative synthesis prevents a formal comparison of effect sizes across interventions. Additionally, the rapidly evolving literature in cancer neuroscience may render some mechanistic insights preliminary, requiring validation through prospective clinical studies. The heterogeneity of cancer types, stages, and treatment modalities further complicates the generalizability of findings across all cancer pain populations.

5. Conclusions

Cancer pain arises from a complex interplay between malignant tissue, the skeletal or visceral microenvironment, and the nervous system. Key neurobiological themes include (i) peripheral sensitization by tumor/stromal mediators and acidic/ATP-rich milieus, (ii) pathological nerve remodeling and PNI, (iii) chemotherapy-driven neural injury, and (iv) central glial-chemokine-mediated plasticity. These mechanistic insights already guide practice (e.g., anti-resorptives and radiotherapy in bone pain) and are spawning new approaches, from TRPV1-targeted neuroablatives to chemokine and purinergic antagonists. Future progress hinges on rigorous phenotyping, translational trials that pair mechanism with target, and integrated care pathways that address both pain biology and cancer control.

Abbreviations

Acknowledgments

The authors are grateful to Fondazione Paolo Procacci for the valuable discussions during the development of this review and for the assistance provided throughout the publication process.

Author Contributions

Conceptualization, G.V.; Methodology, G.V., M.L.G.L.; Writing—Original Draft, G.V., R.G.; Writing—Review & Editing, M.L.G.L., G.F., A.C., A.A.A.A., M.M., J.V.P. All authors have read and agreed to the published version of the manuscript.

Competing Interests

The authors declare no conflicts of interest.

Data Availability Statement

The data supporting the conclusions of this narrative review are derived from published literature sources cited throughout the manuscript. All references and their corresponding data are publicly available through their respective journals and databases. Additional information regarding the literature search strategy, study selection criteria, or data extraction processes are available from the corresponding author upon reasonable request.

AI-Assisted Technologies Statement

During the preparation of this manuscript the authors used ChatGPT in order to improve the language. After using this tool/service, the authors reviewed and edited the content as needed and take full responsibility for the contents of the published article.

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