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Abstract

Given that the incidence of cancer is dramatically increasing nowadays, cancer-related neuropathic pain including tumor-related and therapy-related pain gradually attracts more attention from researchers, which basically behaves as a metabolic-neuro-immune disorder with worse clinical outcomes and prognosis. Among various mechanisms of neuropathic pain, the common underlying one is the activation of inflammatory responses around the injured or affected nerve(s). Innate and adaptive immune reactions following nerve injury together contribute to the regulation of pain. On the other hand, the tumor immune microenvironment involving immune cells, as exemplified by lymphocytes, macrophages, neutrophils and dendritic cells, inflammatory mediators as well as tumor metastasis have added additional characteristics for studying the initiation and maintenance of cancer-related neuropathic pain. Of interest, these immune cells in tumor microenvironment exert potent functions in promoting neuropathic pain through different signaling pathways. To this end, this review mainly focuses on the contribution of different types of immune cells to cancer-related neuropathic pain, aims to provide a comprehensive summary of how these immune cells derived from the certain tumor microenvironment participate in the pathogenesis of neuropathic pain. Furthermore, the clarification of roles of various immune cells in different tumor immune microenvironments associated with certain cancers under neuropathic pain states constitutes innovative biology that takes the pain field in a different direction, and thereby provides more opportunities for novel approaches for the prevention and treatment of cancer-related neuropathic pain.

Keywords

Neuropathic pain cancer immune cells tumor immune microenvironment macrophages T cells neutrophils dendritic cells

Introduction

Neuropathic pain, as a common pattern of chronic pain, is characterized by spontaneous pain and mechanical allodynia, mechanistically attributed to neuroinflammatory and neuroplastic changes that damage the somatosensory system.^1,2,3 Many patients with spinal cord injury, stroke, infections, and diabetes, etc., are accompanied by this prevalent symptom, in turn affecting their quality of life as well as their ability to receive effective treatment.^4,5,6,7 Of note, neuropathic pain presents in 39% of cancer patients, which has been well recognized as cancer-related neuropathic pain and studied recently.^8,9,10 In terms of specific causes, the cancer development, paraneoplastic reactions and treatment such as chemotherapy drugs can lead to neuropathic pain in cancer patients, and different types of pain have personalied treatments.^11,12,13 Taking breast cancer for example, the causes of pain include surgical outcome, tumor spread, bony metastasis to the spine, and chemotherapy.^14,15 It is worthy to mention that cancer-related neuropathic pain is generally associated with poor outcomes.^16,17 Of interest, Rayment et al. have reported that cancer patients with neuropathic pain have worse physical, cognitive, and social functioning.¹⁶

Speaking of molecular mechanisms, the induction of inflammatory reactions at the site of the damaged or affected nerve(s) is one of the most common underlying mechanisms of cancer-related neuropathic pain, with taking inflammation at center.^18,19,20 Immune cells, for example macrophages, T cells, neutrophils, dendritic cells and natural killer (NK) cells have been shown to play a role for development, maintenance and recovery of cancer-related neuropathic pain and therefore are attractive targets for novel pain therapies.^21,22 In particular, microglia are activated in the dorsal horn and peripheral immune cells infiltrate the nervous system to promote chronic neuroinflammation and contribute to the initiation and progression of cancer-related neuropathic pain, in both mice and humans, as nicely reviewed by Bethea and Fischer in 2021.²³ Importantly, immunity not only controls pain development and maintenance, but is also necessary for pain resolution. Bethea together with Fischer have summarized the interactions of the peripheral immune system with the nervous system, and sketch their contribution to the development and recovery of pain.²³ As for the treatment, combinations of analgesics are promising, whereas evidence for cannabinoids is meager.^24,25 At present, due to its pathophysiological process and molecular mechanisms of cancer-related neuropathic pain remaining unclear, there is a lack of prevention measures and effective treatments.

On the other hand, cancer itself has plenty of particularities. The tumor microenvironment contributes to tumorigenesis, tumor progress, tumor metastasis, tumor immune resistance, tumor chemotherapy, and tumor immunotherapy.^26,27,28 Of interest, there are plenty of functional interactions between the tumor and the host in the tumor immune microenvironment, which thereby determine the initiation and progression of cancer.^29,30 Various immune cells exist within the microenvironment, such as tumor-infiltrating lymphocytes, tumor-associated macrophages, tumor-infiltrating neutrophils, and tumor-infiltrating dendritic cells, etc,^31,32 which exert distinct properties via affecting various signaling pathways. For example, recent research data from Wang et al. have demonstrated that dendritic cells in the tumor microenvironment from lung adenocarcinoma aggravates the neuropathic pain via promoting the secretion of paracrine inflammatory and growth factors.³³ Based on this, immunosuppression of some components from the tumor microenvironment can be another critical barrier for the antitumor immunity to some extent, and the similar case is for the management of cancer-related neuropathic pain. For this purpose, this review aims to summarize current knowledge of cancer-related neuropathic pain with special focus on the involvement of immune cells thereof, address some advantages as well as limitations based on recent studies, and further provide some insights into deeper exploration on effective preventive and therapeutic measures of cancer-related neuropathic pain.

General overview of cancer-related neuropathic pain

First of all, cancer-related neuropathic pain and cancer neuropathic pain are different concepts. The aetiology of cancer-related neuropathic pain is diverse, which is conventionally subdivided into tumour-related and treatment-related pain. For sure, not all pain in cancer patients can be cancer-related, as exexplified by comorbid disease-related pain, particularly in older patients.^8,34 As reported, around 60%–70% of neuropathic pain in cancer patients is related to tumour itself, i.e. cancer neuropathic pain, ∼20% of cases happen due to cancer treatment, and about 10%–15% of cases suffer from comorbid diseases, such as diabetes, cardiovascular diseases, etc.³⁵ The overview of these three subtypes of pain in cancer patients is given in Table 1. In this review, we mainly discuss cancer neuropathic pain, which is the most common pattern of pain in cancer patients. In addition to cancer neuropathic pain, treatment-related pain, acting as an unintended consequence or complication of chemotherapy, surgery, and radiotherapy,^36,37,38 is also briefly mentioned, and listed in Table 1. Even though treatment-related pain usually apprears due to applied therapies, this symptom can still persist for a long time after treatment.³⁹ Next, the involvement of immune cells in cancer-related neuropathic pain is mainly studied in the context of these two subtypes of pain, as summarized in Figure 1 and Table 2.

Table 1.

Types of neuropathic pain in cancer patients.

Types of pain	Aetiology	Incidence	Clinical features	Mechanisms
Tumour-related pain	Cancer neurapathic pain	60%–70%	The most common pattern	Direct infiltration by the primary tumour or metastases into components of the peripheral or central nervous system
Treatment-related pain	Cancer treatment, for example chemotherapy, surgery, and radiotherapy	20%	Individual differences	Side effects or complications from cancer treatments
Comorbid disease-related pain	Comorbid diseases, such as diabetes, cardiovascular diseases	10%–15%	Particularly in older patients	Complications of comorbid diseases

Figure 1.

Roles and detailed mechanisms of different types of immune cells in cancer-related neuropathic pain. Depicted are specific roles and molecular mechanisms of tumor-associated macrophages (a), tumor-infiltrating T cells (b), neutrophils (c), and dendritic cells (d) in the development of cancer-related neuropathic pain. Most of publications have studied tumor-associated macrophages in cancer-related neuropathic pain, demonstrating that macrophages contribute to osteosarcoma, colorectal cancer, and solid tumors via different machanisms (a). There are a few studies for tumor-infiltrating T cells, neutrophils, and dendritic cells, whereas still displaying their functional involvement mainly associated with inflammatory regulation (b–d).

Table 2.

The involvement of different types of immune cells in cancer-related neuropathic pain.

Types of immune cells	Types of tumors	Effects on neuropathic pain	Mechanisms	References
Tumor-associated macrophages	Osteosarcoma	Macrophages recruitment contribute to cancer-evoked pain	Via targeting β2-and β3-adrenergic receptors	⁵³
	Colorectal cancer	α7 nicotinic acetylcholine receptor in macrophages inhibits neuropathic pain	Through the JAK2/STAT3 signaling pathway	⁴⁷
	Some solid tumors	DRG infiltration by macrophages contributes to paclitaxel induced peripheral neuropathy	Via the activation of TLR4 signaling and increased MCP-1 expression	⁵⁷
Tumor-infiltrating lymphocytes	Neuroblastoma	The 4SCAR-GD2 T-cell therapy demonstrated antitumor effect, but induced neuropathic pain	GD2 acts as an effective target for neuroblastoma immunotherapy	⁴⁹
	Bone cancer	Imbalanced spinal infiltration of Th17/Treg cells contributes to bone cancer pain	Imbalanced Th17/Treg cells promote microglial activation	⁷⁰
	Some solid tumors	CD8⁺ T cells and IL-10 are essential for resolution of CINP	CD8⁺ T cells increase IL-10 receptor in DRG	⁷¹
Tumor-associated neutrophils	Osteosarcoma	EA-2X/3 treatment reduces tumor-induced hyperalgesia	EA-2X/3 elicits a decrease in tumor-associated inflammation	⁴⁸
Tumor-associated neutrophils	Osteolytic breast carcinoma	SerpinA3N acts against induction of neuropathic pain	SerpinA3N inhibits the T-cell- and neutrophil-derived protease	⁷⁶
Tumor-infiltrating dendritic cells	Lung adenocarcinoma	Tumor-infiltrating dendritic cells promote neuropathic pain	Dendritic cells boosts paracrine inflammatory and growth factors	³³

Abbreviations: TLR4, Toll-like receptor 4; MCP-1, monocyte chemotactic protein 1; DRG, dorsal root ganglion; CINP, chemotherapy-induced neuropathic pain; EA, electroacupuncture; GD2, disialoganglioside 2; JAK2, Janus tyrosine kinase 2; STAT3, signal transducer and activator of the transcription 3; Th17, T helper 17; Treg, regulatory T.

In fact, the presence of cancer-related neuropathic pain is as a result of direct infiltration by the primary tumour or metastases into components of the central or peripheral nervous system.^40,41 Bony metastatic disease leads to vertebral collapse, causing spinal cord compression, which is a typical example of involvement of the central nervous system.⁴² Invasion of the brachial plexus by thoracic tumours is a common example of involvement of the peripheral nervous system.⁴³ In addition, remote effects of cancer on the immune system activate inflammatory cascade, which would also exacerbate cancer metabolism and the injury of nerves further.⁴⁴

Notably, cancer-related neuropathic pain shares most of common clinical features with classical neuropathic pain, include shooting, sharp, stabbing, tingling, pricking, electric shocks and pins as well as needles.⁴⁵ However, it is increasingly recognised that neuropathic pain actually comprises a range of different subgroups sensory profiles,⁴⁶ which might be attributed to different neurobiological mechanisms, and respond differently to treatments tailored to these. Therefore, to figure out specific molecular mechanisms of cancer-related neuropathic pain is essential for its effective prevention and treatment.

The involvement of immune cells in cancer-related neuropathic pain

Current original studies together suggests that major immune cells involved in cancer-related neuropathic pain encompass tumor-associated macrophages, tumor-infiltrating T cells, and neutrophils as well as dendritic cells.^33,47,48,49 Their roles and detailed mechanisms are vividly visualized in Figure 1 and listed in Table 2 according to cell types, which will also be comprehensively described in the following subchapters.

Role of tumor-associated macrophages in cancer-related neuropathic pain

So far, it has been acknowledged that peripheral monocytes that differentiate into macrophages upon tissue infiltration play a potent role in the intiation and development of neuropathic pain.^50,51,52 In this subchapter, several original studies addressing the role of tumor-associated macrophages in neuropathic pain will be especially discussed in the context of different kinds of cancers, and some well-described mechanisms are also illustrated in Figure 1(a).

Recent findings from Bruno et al. have revealed that β2-and β3-adrenergic receptor (AR)-expressed neural macrophages contribute to cancer-evoked pain through utilizing the K7M2 osteosarcoma-bearing mouse model.⁵³ In their study, the progression of mechanical allodynia elicited by oxidative stress is closely associated with the recruitment of neural macrophages. Importantly, the antagonism of β2-and β3-ARs is found to not only result in the supression of tumor growth, but also in cancer pain, together highlighting the therapeutic potential of the β2-and β3-ARs signaling against osteosarcoma-evoked pain.⁵³ Through using human monocyte-derived macrophages, Fei et al. have demonstrated that α7 nicotinic acetylcholine receptor (α7nAChR) in tumor-associated macrophages suppresses colorectal cancer (CRC) metastasis and relavant pain signaling.⁴⁷ When co-culturing with LoVo cells, a commonly-used CRC cell line, the knockdown of α7nAChR in macrophages dramatically attenuated the phosphorylation of STAT3, p85 as well as p65. Furthermore, suppression of JAK2/STAT3 prohibited the migration ability of LoVo cells, which was enhanced by the α7nAChR-siRNA knockdown. These in vitro results address the important role of α7nAChR-expressed tumor-associated macrophages in preventing CRC metastasis, regulated by the JAK2/STAT3 signaling pathway.⁴⁷ The above-mentioned two studies together display the role of tumor-associated macrophages in cancer neuropathic pain.

In addition to cancer neuropathic pain, the role of tumor-associated macrophages in treatment-related neuropathic pain has been also studied, another common pattern of cancer-related neuropathic pain. Zhang and coworkers used Sprague-Dawley rats to show that macrophage infiltration occurs in a time course, which was in consistent with the onset of the behavioral phenotype of chemotherapy-induced peripheral neuropathy (CIPN). As one of the most effective chemotherapeutic drugs, paclitaxel is popularly applied for the treatment of solid tumors for example breast cancer, ovarian cancer, and non-small cell lung carcinoma.^54,55,56 Of note, dorsal root ganglion (DRG) infiltration by macrophages contributes to paclitaxel-induced peripheral neuropathy through activating Toll-like receptor 4 (TLR4) and upregulating monocyte chemotactic protein 1 (MCP-1) expression, which for the first time stresses a mechanistic link that TLR4 activation followed by MCP-1 elevation by DRG neurons leads to macrophage infiltration to the DRG during the development of behavioral signs of CIPN.⁵⁷ Moreover, Old et al. have reported vincristine sulfate (VCR) treatment can improve the adhesion property of endothelial cells, leading to the infiltration of circulating CX3CR1 + monocytes into the sciatic nerve, which has been observed for a murine model of vincristine-induced neuropathic pain. Interestingly, the chemokine CX3CL1 activates CX3CR1 + monocytes at the endothelial-nerve interface, and this interaction further induces reactive oxygen species production, which activates the receptor TRPA1 in sensory neurons, and evokes the pain response. In the meanwhile, Cx3xr1-deficient mice show a delay in the development of allodynia following VCR administration.⁵⁸ In addition to ligand-receptor interactions, functional data from Montague et al. have also indicated an interaction between CX3CR1 and the chemokine receptor CCR2 in monocytes, being a novel mechanism for chemotherapy-induced pain as well as a promising target. Besides, the significance of CCL2/CCR2 signalling in VCR-induced pain has been observed for Cx3xr1-deficient mice.⁵⁹

From a clinical perspective, Chen et al. have confirmed the significance of tumour-associated macrophages in pancreatic ductal adenocarcinoma (PDAC) patients through a retrospective analysis. Of note, the incidence of abdominal pain in PDAC patients is found to relate to the count of tumour-associated macrophages. In other words, PDAC patients with higher tumour-associated macrophages are tend to have abdominal pain. In addition, the higher infiltration by M2 macrophages is accompanied by the lower survival rate of these patients, suggesting the polarization of M2 macrophages may participate in neural invasion.⁶⁰ In combination with experimental data described in the above paragraphs, these studies together verify the role of tumor-associated macrophages in cancer-related neuropathic pain, and clarify at least partially molecular mechanisms involved in this pathological process under cancer states.

Role of tumor-infiltrating lymphocytes in cancer-related neuropathic pain

Next to monocytes/macrophages, infiltrating lymphocytes, mainly regulatory T (Treg) cells, a subpopulation of T lymphocytes with immune regulatory functions, have been found to be important contributors to the pathology of neuropathic pain.^61,62,63,64 Given that T cells function as important players in the adaptive immune system, underlining T cells have been also shown to contribute to the transition from acute to chronic pain.⁶⁵ Of interest, specific subsets of T cells can release lots of mediators, for example inflammatory cytokines as well as endogenous opioid peptides, which finally enhance, inhibit or resolve pain under different states.^66,67

Huo and colleagues have revealed that Treg cells are transiently increased in the spinal cord of a mouse model of bone cancer pain (BCP), followed by an imbalance towards T helper 17 (Th17) cells. In fact, an increasing body of evidence have shown that TH17 cells are related to increased pain sensitivity and persistent pain, whereas Tregs are mainly involved in the endogenous recovery of pain.^68,69 In their study, elevated IL-17/IL-17A levels promote the microglial activation and further exacerbate pain intensity. In a similar vein, the injection of IL-17/IL-17A neutralizing antibodies ameliorates BCP, with lower Th17/Treg infiltration as well as less microglial activation. These in vitro as well as in vivo results together identify the imbalanced Th17/Treg infiltration as a new mechanism for the development of BCP.⁷⁰ In clinical practice, Yu et al. have tested chimeric antigen receptor (CAR) disialoganglioside 2 (GD2)-specific (4SCAR-GD2) T cells for treatment of refractory or recurrent neuroblastoma (NB) patients, and found that the 4SCAR-GD2 T-cell therapy could induce mild neuropathic pain in these patients, indirectly suggesting the involvement of T cells with the expression of GD2 in promoting the intiation of pain.⁴⁹

On the other hand, Krukowski et al. have identified CD8⁺ T cells and endogenous interleukin (IL)-10 as potent factors for resolution of CIPN. Interestingly, paclitaxel treatment upregulates the expression of IL-10 receptor in DRG neurons, which needs the presence of CD8⁺ T cells. However, IL-10 inhibits these spontaneous discharges induced by paclitaxel in order to accelerate the recovery from CIPN.⁷¹ In a similar vein, a clear shift of T-cell subsets towards the anti-inflammation type has been observed in patients with neuropathic pain, giving additional robust evidence that T cells are extensively involved in pain development.⁶¹ Collectively, contribution of T cells to cancer-related neuropathic pain is mainly attributed to the inflammatory regulation.

Role of tumor-infiltrating neutrophils in cancer-related neuropathic pain

In general, neutrophils are recruited into infected organs and/or tissues via chemokines to protect against inflammation as well as infection at the early satge. Later on, the dysregulation of neutrophil chemotaxis as well as activation is found to contribute to multiple diseases, including cancer.^72,73 Of note, a larger number of tumor-infiltrating neutrophils maintaining the tumor immune microenvironment are significantly associated with worse outcome and prognosis of different cancers, as exemplified by CRC.^74,75 In hindsight, considering that whether tumor-infiltrating neutrophils are involved in cancer-related neuropathic pain remains poorly understood, this subchapter would discuss a limited number of preliminary experimental studies here, in order to give some indications for future research in this field.

Smeester et al. have investigated the therapeutic effect of electroacupuncture (EA) on murine osteosarcoma-induced hyperalgesia, and demonstrated that EA-2X/3 treatment could significantly downregulated tumor-associated inflammation, as shown by reduced tumor-associated neutrophils as well as decreased tumor-associated prostaglandin E2 (PGE2) in these microperfusate samples. Based on this, it is reasonably speculated that tumor-associated neutrophils contribute to osteosarcoma-induced hyperalgesia, which is associated with PGE2-elicited inflammatory effects in terms of mechanisms.⁴⁸ Moreover, Bali and Kuner have identified SerpinA3N, a serine protease inhibitor, through a genetic screen, and showed that SerpinA3N functions against induction of osteolytic breast carcinoma-mediated neuropathic pain via suppressing the T-cell- and neutrophil-derived protease. The similar phenotype has been observed for painful diabetic neuropathy.⁷⁶ In addition to cancer-related neuropathic pain, neutrophils are also investigated in the context of autoimmune disease-related pain.⁷⁷ Harada and colleagues have revealed that cathepsin E (CatE) in neutrophils results in the generation of mechanical allodynia through utilising a mouse model of multiple sclerosis (MS). In their study, accumulated neutrophils in DRG, and CatE-dependent secretion of elastase in these neutrophils were observed, together suggesting a new therapeutic strategy for pain in patients with MS.⁷⁷

At last, it is especially worthy to mention that neutrophils exert a unique property of releasing chromatin reticulum, i.e. neutrophil extracellular traps (NETs). This function can support that circulating tumor cells enter the vascular system, and further promote the invasion as well as metastases of tumor cells.^78,79,80 This could be another plausible explanation for how tumor-infiltrating neutrophils mechanistically lead to cancer-related neuropathic pain. In summary, it remains unclear how tumor-infiltrating neutrophils regulate cancer-related neuropathic pain, which still needs more experimental and clinical evidence to elucidate further.

Role of tumor-infiltrating dendritic cells in cancer-related neuropathic pain

In the last subchapter of this review, the role of tumor-infiltrating dendritic cells in cancer-related neuropathic pain will be discussed. The functions of dendritic cells, a type of antigen-presenting cells, mainly include capturing antigens from pathogens or tumors, and presenting antigens to T cells for immune response.^81,82 Abnormal metabolic changes of tumor cells lead to further modifications in the microenvironment, which in turn prohibit the function of dendritic cells and result in the occurrence of tumor immune escape.^83,84,85

Wang et al. have demonstrated the contributions of the infiltrated dendritic cells insulted by Wnt1 in tumor microenvironment to neuropathic pain associated with lung adenocarcinoma.³³ Of special note, they applied single-cell RNA-seq in infiltrated dendritic cells from lung adenocarcinoma, showing thousands of upregulated genes in the tumor microenvironment and some enriched genes in pain pathway. Several paracrine facors for eample WNT10A, TNF, PDGFA, and NRG1 are found to be increased in tumor-infiltrating dendritic cells. Similar changes are observed for the receptors of these paracrine factors were in DRG, and these changes still keep in pain conditions. These reults together indicate that infiltrated dendritic cells in tumor microenvironment promotes neuropathic pain by sensitizing nociceptor sensory neurons via paracrine factors. Furthermore, blockage of paracrine factor signaling might alleviate cancer pain, providing a new avenue for resolving cancer-related neuropathic pain by targeting dendritic cells.³³ Another study by Maganin et al. have revealed a novel role for dendritic cells driving non-cancer neuropathic pain development through elevation of the kynurenine metabolic pathway. They employed the spared nerve injury model, and stressed the importance of the involvement of dendritic cells in regulating neuropathic pain. This novel paradigm offers potential new targets for drug development against this type of chronic pain.⁸⁶ However, how dendritic cell and T cell are co-regulated in pain development requires more exploration.

Concluding remarks

So far, substantial progress has been made in the prevention as well as treatment of cancer. In contrast, there is a limited number of relevant studies in the assessment and management of neuropathic pain in cancer patients. First of all, it is essential to differentiate neuropathic pain from other properties of cancer-related pains. Because cancer-related neuropathic pain is always associated with worse outcomes and prognosis, and needs different treatment strategies. Secondly, developing a more reliant and systematic diagnostic assessment system is very critical for these patients with cancer-related neuropathic pain, which would further support scientists and clinicians to develop much-needed targeted therapies. On the other side, recent popularly-applied single-cell sequencing techniques in combination with spatial transcriptomics would provide more detailed information for the involvement of different types of immune cells on the single cell level, in addition to traditional methods. At last, a deeper understanding of how immune cells changes when the pain is generated would offer multiple promising targets for prophylactic management of CINP. In the future, it remains to be elucidated in futher investigations how different types of immune cells orchestrate complex regulation for neuropathic pain under cancer states using multiple basic as well as advanced approaches.

Footnotes

Acknowledgements

Not applicable.

Author contributions

HM and WJ conceived and designed the contents, structures and layout of the review article with help from LM. The first draft of the manuscript was written by HM and BL, and edited by ZP and WJ. All authors revised and commented on the manuscript drafts. HM and PZ provided the funding.

Declaration of conflicting interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This work was supported by the project of Jilin Provincial Finance Department (No. 2020SCZT015), and the project of the National Health Commission of Jilin Province (No. 2022LC109) to Zhenxiang Pan, and by the project of Jilin Provincial Finance Department (No. 2020SCZT070), and the project of the Jilin Science and Technology Department (No. YDZJ202201ZYTS613) to He Ma. Figures were created with .

ORCID iD

Jingping Wang

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Contribution of immune cells to cancer-related neuropathic pain: An updated review

Abstract

Keywords

Introduction

General overview of cancer-related neuropathic pain

The involvement of immune cells in cancer-related neuropathic pain

Role of tumor-associated macrophages in cancer-related neuropathic pain

Role of tumor-infiltrating lymphocytes in cancer-related neuropathic pain

Role of tumor-infiltrating neutrophils in cancer-related neuropathic pain

Role of tumor-infiltrating dendritic cells in cancer-related neuropathic pain

Concluding remarks

Footnotes

Acknowledgements

Author contributions

Declaration of conflicting interests

Funding

ORCID iD

References