Nerve growth factor: what can surgeons and oncologists learn from a neurological and psychological biomarker?

Psychological problems usually occur in hospitalized patients, especially those with malignant disease, when they understand their serious condition. For those undergoing long-term antiproliferative treatment, depression might occur due to uncomfortable experiences and negative expectations (Xiong et al. 2022 ). The serum NGF level in outpatients with MDD is significantly lower than that in healthy controls (Maes et al. 2024 ). In addition, NGF might be associated with mild somatic symptoms, e.g., chronic fatigue syndrome and irritable bowel syndrome (Jonsjö et al. 2020 ; Chow et al. 2019 ). Extreme actions, e.g., suicide, are used to measure the severity of depression. Two studies involving autopsies revealed that NGF and TrkA levels were both decreased in the prefrontal cortex and hippocampal regions of the brain tissue of suicide victims (Dwivedi et al. 2005 , 2009 ). However, the relationship between serum NGF levels and depression-related suicidality remains controversial, as Maes et al. supported this relationship, whereas two other independent studies raised objections Zhang et al. ( 2022 ); Dou et al. ( 2018 ); Di Franco ( 2021 ); Sadighparvar et al. ( 2021 ); Qi et al. ( 2022 ); Monje e al. ( 2017 ); Qian et al. ( 2024 ); Alzawi et al. ( 2022 ); Ye et al. ( 2011 ); Chung et al. ( 2018 ); Roh et al. ( 2015 ); Ye et al. ( 2014 ); Xiong et al. ( 2022 ); Maes et al. ( 2024 ); Jonsjö et al. ( 2020 ); Chow et al. ( 2019 ); Dwivedi et al. ( 2005 , 2009 ); Bilgiç et al. ( 2020 ); Maes et al. ( 2023 ); Wiener et al. ( 2015 ). In addition to the different age ranges of the included patients, the reason for this difference might be the NGF expression pattern, as a decrease in NGF levels might have occurred within a short period before the decision to commit suicide, which could be partly attributed to NGF downregulation in the brains of the decedents. Despite the lack of a sufficient theoretical basis, during hospitalizations, decreased serum or plasma NGF levels should be monitored because of the potential risk for dangerous events (e.g., suicide, violence, and neuroticism) and the need for a psychological crisis intervention. However, some exceptions could not be explained. First, NGF could be upregulated in paediatric patients, e.g., children with autism spectrum disorder, probably because of the positive correlation between NGF and the overall developmental status of children. Additionally, no differences were found between children with low and high suicidality. The diagnostic value of decreased NGF levels might be applicable only to adults (Bilgiç et al. 2020 ; Liu et al. 2021a , b ; Gevezova et al. 2022 ; Karayağmurlu et al. 2019 ). Second, when dysphrenia further intensifies, e.g., the conversion from MDD to bipolar disorder, NGF levels often increase, which might be confusing if no specialized medical history or auxiliary examination is provided (Pedrotti Moreira et al. 2019 ). Third, if a patient suffers from mental disorders as well as NGF-secreting neuroendocrine neoplasms, determining the trend for the variation in NGF levels is difficult (Zhang et al. 2022a , b ). Additional related clinical and translational studies are needed. Considering that the NGF-TrkA interaction is involved in pain modulation, two strategies, i.e., targeting NGF or TrkA, have been developed. Selective and nonspecific allosteric TrkA inhibitors have been designed and shown to inhibit NGF-induced neurite outgrowth and regulate arthrodynia (Subramanian et al. 2021 ; Bagal et al. 2018 ). Anti-NGF mAbs, including tanezumab, fulranumab, and other antibodies with only preclinical data, e.g., DS002, huAb45, and 58F10G10H, which function by sequestering NGF from TrkA in a dose-dependent manner, have been widely studied (Liang et al. 2022 ; Liu et al. 2022a , b ; Bannwarth and Kostine 2017 ; Dong et al. 2022 ). In cancerous lesions, certain types of tumour cells secrete NGF, which leads to sensory and sympathetic nerve pathological sprouting and the formation of a neuroma-like structure (Mantyh et al. 2010 ). For some patients with advanced tumours, tumour-derived NGF causes bone tissue remodelling, aggravating local bone pain and pathological fracture (Jing et al. 2023 ). Therefore, anti-NGF mAbs should be applied pre-emptively before histological changes in nerves and bones occur, but compensatory administration could also attenuate cancer pain (Jimenez-Andrade et al. 2011 ). In theory, the antinociceptive effects of anti-NGF mAbs could be better than those of transitional nonsteroidal anti-inflammatory drugs (NSAIDs), but few clinical trials have reported any advantages. Sopata et al. reported that long-term treatment with tanezumab as a complement to daily opioid use slightly relieved metastatic bone cancer pain (10 mg for 8 weeks, up to 40 weeks) (Sopata et al. 2015 ). Slatkin et al. studied fulranumab (9 mg for 4 weeks), yet no significant improvement in antinociception was observed (Slatkin et al. 2019 ). Actually, early in 2010, despite acceptable tolerance and a low discontinuation rate (less than 5–10%), clinical trials of anti-NGF mAbs were stopped by the US Food and Drug Administration (FDA) due to serious adverse effects, including neurological problems (e.g., paraesthesia, hypoesthesia, and extremity pain) and joint-related problems (e.g., arthralgia in the knee and rapidly progressive osteoarthritis) (Bannwarth and Kostine 2017 ). A possible reason might be the comprehensive deprivation of the NGF downstream pathway, especially its neurotrophic and neuroprotective functions. Several technical issues, such as improving antibody specificity, maintaining structural stability in tissue, and avoiding nonfunctional binding to NGF, should be addressed (Porte et al. 2014 ). Additionally, the application of anti-NGF mAbs is restricted by social economics. At the present stage, commercialized monoclonal antibodies require expensive production lines and complex approval processes. Even worse, compared with NSAIDs, anti-NGF mAbs might be overdosed due to uncontrollable biodegradation caused by macromolecular immunogenicity, eventually increasing the cost of therapy. Nonetheless, anti-NGF mAbs are worthy of further investigation for the following reasons. First, NGF maintains sufficient expression of µ-opioid receptors in the central nervous system. Hence, the intrathecal delivery of NGF enhances the analgesic effect of fentanyl on diabetes-related hyperalgesia, which could explain why anti-NGF mAbs exhibit limited antinociceptive effects (Shaqura et al. 2013 ). The maintenance of pain receptors or their regulators by other methods should be considered when anti-NGF mAbs are designed, such as by coupled drugs and epitope replacement. Second, strategies targeting NGF probably have additional antineoplastic effects to improve the patient prognosis. NGF blockade impairs the proliferation of oral cancer cells and relieves the general condition of murine oral cancer models (Dou et al. 2018 ). In addition to its effects on bone sarcoma, NGF blockade also significantly inhibits bone destruction and skin hypersensitivity in animal models (McCaffrey et al. 2014 ; Guedon et al. 2016 ; Hou et al. 2024 ). Targeting NGF is also a potential supplement to traditional anticancer treatment. Anti-NGF mAbs alleviate the peripheral neuropathy caused by chemotherapeutic drugs such as paclitaxel, cisplatin and vincristine (Da Vitoria Lobo et al. 2024 ; Liang et al. 2022 ). Upon doxorubicin chemotherapy, the reactive upregulation of NGF exacerbates drug resistance and cancer pain, highlighting the importance and urgency of targeting NGF (Zuo et al. 2024 ). Third, the precise application of NGF antibodies and inhibitors has been poorly studied. The high affinity for NGF and antinociceptive effects of these agents must be independent of their neurotrophic effects to prevent serious systemic adverse reactions due to nerve damage. One of the important reasons is the insufficient understanding of the pathogenic molecular mechanism of each subgroup of patients, especially the unconventional downstream pathways. For example, cross-sensitization mediated by other proteins, e.g., endothelin-1, should be investigated in patients with sustained cutaneous pain (Khodorova et al. 2018 ). For the patients with malignancies, tissue injuries always occur, such as primary injury by the invasion of cancerous lesions, and secondary injuries by invasive therapeutic manipulation (e.g., skin incision and radical surgery). Tissue damage is followed by a timely wound healing process, including epithelization, fibrogenesis, innervation, and vascularization with unknown precedence orders, unless negative factors, e.g., malnutrition, infection, and nonspecific inflammation, exist (Giuliani et al. 2020 ). When injury to the body surface or accessible deep tissue occurs, wound healing can be expedited by debridement, suturing, and drug intervention. Local NGF administration is an excellent example, especially when nerve injury occurs simultaneously. Unlike in cancerous lesions, NGF-associated pathways are protective when injuries occur. The transdermal application of NGF variants accelerates the recovery of diabetic ulcers by activating the AKT pathway with few hyperalgesic effects (Giuliani et al. 2020 ). Similarly, the transdermal injection of NGF into endochondral regions and tibial fracture calluses activates the Wnt pathway and integrin pathway, contributing to increased trabecular number, connective density, and bone mineral density and ultimately increasing bone healing (Rivera et al. 2020 , 2023 ). Wnt ligands, e.g., Wnt5a, promote the proliferation of SCs and the secretion of NGF and VEGF (Liu et al. 2022a , b ). In some studies, nerve regeneration has been shown to be a leading factor contributing to wound healing compared with epithelial and capillary regeneration. The healing of nerve fibres can be measured by axonal growth, myelination, electrophysiological recovery, target organ innervation, and motor function recovery (Liu et al. 2022a , b ). For example, erectile dysfunction is a common problem for cryotherapy and radical prostatectomy of PC due to concomitant injury of the cavernous nerve. This injury can be relieved by the implantation of adipose-derived stem cells and bioactive fibrous membranes. The former increases the production of NGF to inhibit apoptotic mediators, e.g., cleavage of Caspase 3, whereas the latter selectively binds and captures uNGF (Yang et al. 2015a , b ; Casanova et al. 2023 ). Similarly, transplanting transection-activated sural nerve fascicles into the brains of PD patients could result in neuroprotective effects via NGF secretion and apoptosis inhibition (Chau et al. 2022 ). In this sense, local NGF enhances the adaptive response, as manifested by the upregulation of TrkA on the surface of nerve cells (Cho et al. 2020 ). The poor functional status of local nerve cells may be attributed to multiple factors. During development, NGF expression is promoted in a nerve-independent manner, whereas NGF levels and nerve density decrease synchronously with age (Mahdee et al. 2019 ). Chronic inflammation delays wound healing caused by TNF-α induced by infectious or ischaemic factors. In skin wounds, keratinocytes secrete NGF spontaneously. TNF-α further upregulates NGF expression and increases the distribution of NE receptors, which are sensitive to proinflammatory sympathetic signals and unduly increase NGF production in response, aggravating chronic injuries and pain (Wijaya et al. 2020a , b ). Antiproliferative treatments, such as radiation for nasopharyngeal carcinoma and doxorubicin for breast cancer, also have side effects such as central neurotoxicity and cognitive dysfunction, which can be alleviated by the active and passive upregulation of NGF, e.g., the NGF plus steroids regimen and Carissa macrocarpa extracts, respectively (Liu et al. 2020 ; Orabi et al. 2021 ). Nevertheless, most conclusions are based on animal studies and in vitro assays. More clinical trials are needed.

The diagnostic value of NGF has been studied. In addition to being detected in the peripheral blood and CSF, NGF can be detected in the saliva. Salivary NGF is downregulated in adults with temporomandibular disorder and some obese children (Jasim et al. 2020 ; Tvarijonaviciute et al. 2020 ). A neural cell-cell interaction microchip (NCCIM) was developed to measure NGF levels in real time upon coculture between nerve cells and other target cells, providing convenience for secretome mechanistic research (Abdullah et al. 2020 ). Traditional surgical and drug delivery approaches, e.g., transdermal patches, biological membranes, surgical staplers, and absorbable sutures, might be options for loading NGF to address the anastomotic stoma after radical resection of malignancies, traumatic organ damage, and skin ulceration induced by internal diseases or chemoradiotherapy. NGF can be immobilized and purified from mixtures via chromatography or MG-PEG-NTA-Ni + 2 nanocomposites (Khataminezhad et al. 2023 ; Gu et al. 2020 ). However, natural NGF fails to exhibit optimal biological effects and drug distributions, inspiring an attempt to modify the NGF structure. For example, the NGF derivative R100E could facilitate the healing of nerve endings and skin lesions in individuals with diabetes (Giuliani et al. 2020 ). The NGF structure has also been simplified, e.g., the acetylated human NGF 1–14 sequence (hNGF1-14), to overcome drug delivery restrictions mediated by the BBB (Triaca et al. 2020 ). New delivery by artificial synthetic materials, e.g., liposomes incorporating cardiolipin and phosphatidic acid, contributes to NGF transport through the BBB (Kuo et al. 2019 ). Poly (ethylene glycol) dimethacrylate microparticles loaded with NGF have been developed to treat fractures (Rivera et al. 2023 ). Specific siRNAs targeting NGF are widely studied in PDAC. Gold nanocluster- and cationic perfluorocarbon nanoemulsion-assisted delivery to PDAC lesions overcomes the disadvantages of siRNAs, such as a short circulation lifetime, low tissue specificity, poor tumour penetration, and poor cellular uptake (Lei et al. 2017 ; Ding et al. 2022 ). Bioactive membranes can be implanted into orthotopic lesions or injuries, including polycaprolactone membranes, six bilayers of heparin/collagen membranes, and electroresponsive biohybrid membranes made from Bombyx mori silkworm fibroin and reduced graphene oxide, all of which are able to adsorb and carry NGF, facilitating SC adhesion and neurogenesis (Casanova et al. 2023 ; Magaz et al. 2020 ; Pinzon-Herrera et al. 2020 ). Gene therapy targeting NGF is also an option for local treatment, as recombinant mouse NGF has limited biological activity compared with that of human NGF. Human NGF gene vectors are transfected into murine submandibular glands to establish a human NGF-producing model (Gu et al. 2020 ). Three clinical trials have been conducted on NGF gene therapy for AD. Tuszynski et al. implanted modified autologous fibroblasts, whereas Eriksdotter-Jönhagen et al. implanted an NGF biodelivery device, NsG0202, into the forebrains of AD patients, and the degree of cognitive decline was significantly improved (Tuszynski et al. 2005 ; Eriksdotter-Jönhagen et al. 2012 ). In contrast, Rafii et al. transfected an adeno-associated virus vector carrying NGF into the nucleus basalis of Meynert via intracerebral injection, but no improvement was observed, suggesting that potential nonspecific transfection targets and puncture sites should be adjusted (Rafii et al. 2018 ). Even though the product could be synthesized and released in a limited area, this technique remains to be improved for better safety and more accurate targeting. The clinical trials about NGF and TrkA were summarized in Table  2 (Zhang et al. 2025 ; Pang et al. 2023 ; Munkholm and Arendt-Nielsen 2017 ; Castle et al. 2020 ; Falsini et al. 2016 ; Kim et al. 2015 ; Rafii et al. 2014 ; Martino et al. 2013 ; Blandini et al. 2006 ; Lambiase et al. 2007 ; Roblin et al. 2015 ; Watt et al. 2019 ). Table 2 The clinical trials about NGF and TrkA Authors Country Year Type Disease Study object Topic Conclusion References Zhang et al. China 2025 Prospective Healthy participant NGF Anti-NGF monoclonal antibody The safety and tolerability of the antibody AK115 was favorable Zhang et al. ( 2025 ) Pang et al. China 2023 Retrospective Interstitial cystitis NGF, TrkA Biomarker NGF and TrkA were both independent prognostic factors Pang et al. ( 2023 ) Castle et al. USA 2020 Retrospective Alzheimer’s disease NGF NGF delivery Failed AAV delivery to specific encephalic region might be the cause of death Munkholm ( 2017 ) Slatkin et al. USA 2019 Prospective Cancer NGF Anti-NGF monoclonal antibody Fulranumab failed to improve the antinociception effect Slatkin et al. ( 2019 ) Watt et al. United Kingdom 2019 Prospective Knee osteoarthritis TrkA TrkA inhibitor TrkA inhibitor ASP7962 failed to improve pain or physical function of knee joint Watt et al. ( 2019 ) Rafii et al. USA 2018 Prospective Alzheimer’s disease NGF NGF delivery No improvement was observed by transfecting AAV vector carrying NGF Rafii et al. ( 2018 ) Falsini et al. Italy 2016 Prospective Retinitis pigmentosa NGF NGF preparation The safety and possible efficacy of NGF eye-drops was favourable Falsini et al. ( 2016 ) Munkholm et al. Denmark 2016 Prospective Pain NGF Antinociceptive effect Acidic stimulation aggravates NGF-induced hyperalgesia in muscle tissue Castle et al. ( 2020 ) Kim et al. Korea 2015 Prospective Overactive bladder syndrome NGF Biomarker Urinary NGF is potential biomarkers for therapeutic markers Kim et al. ( 2015 ) Roblin et al. United Kingdom 2015 Prospective Psoriasis TrkA TrkA inhibitor TrkA inhibitor CT327 relieved the pruritus. Roblin et al. ( 2015 ) Sopata et al. Poland and USA 2015 Prospective Metastatic bone cancer NGF Anti-NGF monoclonal antibody Tanezumab slightly relieved metastatic bone cancer pain Sopata et al. ( 2015 ) Rafii et al. USA 2014 Prospective Alzheimer’s disease NGF NGF delivery NGF gene therapy is well-tolerated and feasible by bilateral stereotactic administration Rafii et al. ( 2014 ) Martino et al. Italy 2013 Prospective Major depressive disorder NGF Biomarker Serum NGF is potential biomarkers for therapeutic markers Martino et al. ( 2013 ) Eriksdotter-Jönhagen et al. Sweden 2012 Prospective Alzheimer’s disease NGF NGF delivery Cognitive decline was relieved bt implanting NGF biodelivery devices Eriksdotter-Jönhagen et al. ( 2012 ) Lambiase et al. Italy 2007 Prospective Neurotrophic keratopathy NGF NGF preparation NGF eye-drops contribute to ulcer healing and no circulating NGF antibodies was found Lambiase et al. ( 2007 ) Blandini et al. Italy 2006 Observational Headache NGF Biomarker NGF was potentially involved in the pathophysiology of primary headaches Blandini et al. ( 2006 ) Tuszynski et al. USA 2005 Prospective Alzheimer’s disease NGF NGF delivery Cognitive decline was relieved by implanting modified autologous fibroblasts Tuszynski et al. ( 2005 ) AAV Adeno-associated virus vector The clinical trials about NGF and TrkA AAV Adeno-associated virus vector

NGF serves as a tumour-promoting factor, PNI mediator and indicator of a poor prognosis for patients with cancerous lesions. The biological effect of NGF depends on the sensitivity of target cells, which can be evaluated by two factors, i.e., NGF levels in the microenvironment and the NGF receptor distribution in target cells (Fig.  4 ). The sources of NGF include NGF-secreting tumour cells, peritumoral stromal cells, immune cells, and hyperfunctional nerve cells, leading to a primary increase in local NGF levels. When tissue injuries occur, stress responses induce the release of several cytokines and mediators and subsequently stimulate secondary NGF secretion from the SCs to prolong damaged nerve fibres (Tazawa et al. 2021 ). Compared with primary upregulation, secondary upregulation may be accompanied by more severe nerve injuries, significant neural symptoms, and positive detection of damage biomarkers, e.g., tau protein and chitotriosidase in CSF (Cheung et al. 2018 ). However, whether the invasion of nerve fibres results in the compensatory expression of NGF is still unknown. Fig. 4 Hypothesis of the potential molecular mechanisms according to the expression level of NGF and TrkA receptor Hypothesis of the potential molecular mechanisms according to the expression level of NGF and TrkA receptor The membrane abundance of TrkA can be regulated flexibly by ProNGF and NGF, but the main determining factor is the tissue type. NGF and TrkA abundance should be measured before NGF-related antiproliferative therapy is administered (Fig.  5 ) (McCall et al. 2011 ; Wu et al. 2016 ). For malignancies characterized by the positive expression of NGF and TrkA, the communication between nerve cells and cancer cells forms a positive feedback loop by conventional autocrine and paracrine signalling, leading to the rapid progression of PNI and distal metastasis. In contrast, the progression of malignancies with negative expression of NGF and positive expression of TrkA can also be promoted, but the feedback mechanism is ambiguous. In theory, malignancies with little expression of NGF and TrkA can be regulated by secreted proteins but not neurotrophins. This extracellular protein might be released from either nerve cells or other downstream cells that communicate with nerve cells. Fig. 5 Presentation of the expression level of NGF and NGF receptors in different tissue. IFNGR is widely expressed in human tissues. Hence, IFNGR is selected for positive control. The expression profiles were contributed by McCall et al. and downloaded from BioGPS database ( http://biogps.org/ ). The gradual change from red to blue represents changes in gene expression from high to low Presentation of the expression level of NGF and NGF receptors in different tissue. IFNGR is widely expressed in human tissues. Hence, IFNGR is selected for positive control. The expression profiles were contributed by McCall et al. and downloaded from BioGPS database ( http://biogps.org/ ). The gradual change from red to blue represents changes in gene expression from high to low NGF has functions in both promoting tumour progression and maintaining the homeostasis of normal structures. Hence, the systematic application of NGF or anti-NGF for any purpose may not be the optimal solution, even though murine NGF has been allowed for preventing optic nerve injury and N-hexane poisoning via intramuscular injection. First, systematic application increases the probability of neutralizing autoantibody formation, impairing the therapeutic effect to some degree. Second, TrkA is widely expressed, such that any change in the overall NGF level is a possible cause of adverse events, e.g., fever, pruritus, erythema, muscular pain, diarrhoea, and liver dysfunction. Third, NGF application might be a potential cause of malignant transformation, albeit with no direct evidence available at present. Local treatment should be focused on because of its advantages of timely, specific, and adaptive effects on the physiological NGF function rhythm. However, the detailed mechanisms of the TrkA-dependent and -independent effects of NGF are not fully understood, especially the key factors that determine the direction of flow to either oncogenic or neurotrophic pathways, the exact role of perifocal participants in cellular communication, and the reason for the differences in NGF expression among different organs. More clinical trials and development projects are welcomed for better application of NGF, a pleuripotent but conserved cytokine.

Malignant tumours constitute one of the major diseases that endangers the health and life of people worldwide and remain to be addressed (Siegel et al. 2024 ). Surgery is the best option for cancer patients in the early stages, but postoperative recurrence is a Gordian knot (Reticker-Flynn and Engleman 2023 ). Currently, despite great progress in treating cancerous diseases, e.g., chemotherapy, radiotherapy, immunotherapy and targeted therapy, morbidity and mortality remain high due to tumour heterogeneity, resistance to comprehensive treatments, nonspecific clinical symptoms, and a delayed diagnosis (Setiawan et al. 2023 ). A high propensity for the metastasis of malignancies is the leading cause of cancer-related death and is difficult to address because of the characteristics of vascular invasion, lymph node metastasis, perineural invasion, etc. (Ohtsuka et al. 2002 ). An urgent need is to understand the molecular mechanisms of the pathogenesis and development of cancerous lesions to find new diagnostic and therapeutic approaches. One of the possible reasons is the dysfunctional tumour microenvironment (TME), which is composed of several cell types (e.g., immune cells and fibroblasts) and distinct expression patterns of protein subgroups (e.g., rearrangement of surface proteins and abnormal secretion of cytokines) (Yang et al. 2023 ; Kirchhammer et al. 2022 ). Nerve growth factor (NGF) is the first discovered member of the neurotrophin family and promotes the growth and survival of peripheral sensory and sympathetic neurons. Additionally, as a significant cytokine, NGF functions to fine-tune the activation status of stromal cells and the proliferation and differentiation of epithelial cells and neural stem cells (Rocco et al. 2018 ). Abnormal NGF expression and secretion are detected in the body fluids of patients with neurological and psychological disorders, such as viral encephalitis, neurogenic bladder disease, schizophrenia, and Alzheimer’s disease (Turkmen et al. 2021 ; Rauch et al. 2022 ; Florentinus-Mefailoski et al. 2021 ; Homma et al. 2013 ). In addition to nervous system neoplasms, NGF is involved in the malignant transformation of other tissue cells, partly via nerve fibres and their secretory proteins near primary and metastatic cancerous lesions. Superfluous NGF in TME influences the biological behaviour of cancer cells (e.g., tropism and proliferation), which is called tumour neurotrophic activity (Banh et al. 2020 ). Additionally, nerve-derived NGF enhances perineural invasion (called PNI or axon-guidance activity) and ultimately results in the irritative and disabling symptoms of certain types of malignancies (Ricci et al. 2022 ). PNI was verified to be an unfavourable independent indicator of the survival of patients with malignancies such as pancreatic cancer, colorectal cancer (CRC) and gallbladder cancer (Newhook et al. 2023 ; Park et al. 2023 ; Pai et al. 2022 ). Therefore, the value of NGF is not restricted to its function as a neurological and psychological biomarker and is worthy of study for clinical application in oncology wards. In this review, we focused on recent and previous mechanistic studies and clinical trials of NGF, especially the role of NGF in the crosstalk between nerve cells and malignant cells such as digestive system neoplasms. First, the molecular mechanisms of NGF and related signalling pathways are discussed. Second, achievements in research on NGF in neurological and psychological disorders are summarized. Next, we compared the updated findings of NGF in cancerous lesions to look for similarities and universalities. Finally, we reviewed and proposed possible future directions for the application of NGF.