Mechanisms of neuropeptide-mediated immune sensing in the modulation of antitumor immunity

Abstract

The hallmarks of cancer, first introduced by Hanahan and Weinberg in 2000 and updated in 2011 and in 2022, summarize the core processes that drive the stepwise development of tumors. This framework has proven highly effective for interpreting the vast complexity of cancer and its underlying biology. However, advances in spatially resolved single-cell technologies and more advanced imaging approaches have revealed additional layers of regulation that shape tumor behavior, particularly involving interactions between tumors and the nervous system. Although the influence of innervation on tumor cells and tumor vasculature has been widely studied, the impact of neurotransmitters, neural-derived factors, or neuropeptides on tumor-infiltrating immune cells remains largely unexplored and unexploited. Importantly, immune cells within the tumor microenvironment express receptors for various neural-derived signals, and can shift their phenotypes and adapt their functions in response to these inputs. Here, we highlight neuropeptide-driven pathways that modulate tumor-infiltrating immune cells to influence hallmark functions and, ultimately, shape tumor progression. Neural regulation of the tumor microenvironment is therefore emerging as a promising and potentially targetable layer that could complement existing cancer therapies.

Introduction

Despite constant progress in therapies in the past decades, cancer remains a deadly and challenging disease to treat due to its complex interactions both locally within the tumor microenvironment (TME) and systemically across multiple organs and physiological systems.¹ In this context, the peripheral nervous system (PNS) has gained increasing attention over the past decades. Cancer neuroscience has emerged as a field that expands the classical view of tumor biology by recognizing neural components as active regulators of carcinogenesis, cancer progression, and metastasis.² The nervous system and the TME exert a complex and bidirectional relationship, in which tumors can actively recruit and remodel nerve fibers, resulting in increased innervation,³ while nerve-derived factors, in turn, shape the behavior of tumor, vascular, stromal, and immune cells.² Among these factors, neuropeptides have been highlighted as key mediators of neuroimmune communication in cancer. Neuropeptides are small, bioactive signaling molecules produced primarily by neurons, although they can also be secreted by tumor, stromal, and immune cells,^{4 5} acting mainly through G protein-coupled receptors (GPCRs). In the context of cancer, neuropeptides have been associated with tumor progression, where they can promote angiogenesis, enhance metastatic potential, and modulate cellular survival pathways.^5–8 Additionally, immune cells are now recognized as important targets of neuronal signaling within the TME. Multiple innate and adaptive immune populations, including dendritic cells (DCs), macrophages, natural killer (NK) cells, innate lymphoid cells (ILCs), and T lymphocytes, express receptors for neuropeptides and respond to nerve-derived signals, altering their recruitment, differentiation, and effector functions.^9–12

Although numerous neuropeptides regulate immune responses, this review focuses on neuropeptides with established roles in antitumor immunity, together with candidates that are dysregulated in cancer and possess well-characterized immunomodulatory functions outside the cancer setting, highlighting emerging avenues for future investigation.

Substance P

Substance P (SP), a member of the tachykinin family, was first discovered in 1931 but only formally isolated in the 1970s.¹³ SP is encoded by the TAC1 gene and is synthesized as a precursor peptide that is subsequently processed into its mature form, an 11-aa neuropeptide.¹⁴ SP is primarily secreted by nociceptor neuronal terminals in both central nervous system (CNS) and PNS, but it can also be released by immune, epithelial, endothelial, smooth muscle, and mesenchymal stem cells.¹⁵ SP exerts its biological effects mainly through its high-affinity receptor, neurokinin-1 receptor (NK1R), a GPCR widely expressed in neuronal, endothelial, immune, and cancer cells. Binding of SP to NK1R triggers receptor internalization, thereby regulating receptor recycling and desensitization. However, SP can also signal through Mas-related G protein-coupled receptors (MRGPRs), these non-canonical receptors mediate important cell- and context-specific immunoregulatory effects of SP.^{16 17} While the main functional role of SP is pain transmission and perception,¹⁸ activation of NK1R also stimulates several intracellular signaling pathways, including PI3K-AKT, NF-κB, Wnt-βcatenin, and MAPK-ERK.^{15 19} These signals are involved in numerous physiological and pathological processes, particularly those associated with tumor cell biology, such as cell proliferation, migration, survival, angiogenesis, resistance to apoptosis, and pro-inflammatory cytokine secretion.⁶ The role of SP and NK1R signaling has been extensively investigated across a wide range of cancers, including breast, ovarian, lung, thyroid, pancreatic, prostate, glioma, colorectal, head and neck, melanoma, and leukemia.^{6 14 20} Despite differences in tissue origin and stromal composition, SP seems to consistently contribute to the establishment of a pro-inflammatory microenvironment. It can act directly via neuronal release onto tumor cells or indirectly through tumor cell-derived secretion, functioning in both autocrine and paracrine signaling loops. In these contexts, SP promotes tumor growth while modulating surrounding stromal and immune cells. Additionally, SP can exert systemic effects through endocrine-like signaling by entering the circulation and influencing distant tissues.¹⁹

In the context of immunity, SP plays a significant role in immunomodulatory functions across both innate and adaptive immune compartments.²¹ It has been shown that NK1R activation enhances immune cell migration in vitro. Specifically, SP-NK1R signaling promotes macrophage inflammatory protein production in human T cells²² and directly induces chemotactic responses in immune populations such as human eosinophils.²³ These findings support a broader role for NK1R in regulating immune cell recruitment and inflammatory responses. Within the innate immune niche, SP and NK1R agonists enhance macrophage activation and increase IL-12 production in murine models.^24–26 Moreover, SP promotes neutrophil activation and phagocytosis in humans.^{27 28} Regarding DCs, SP improves immunostimulatory capacity in skin-resident DCs in mice.²⁹ Additionally, NK1R activation decreases IL-10 synthesis while increasing IL-12 production, thus skewing immune responses toward a type 1 profile and promoting homing to the draining lymph node (dLN).³⁰ Also, SP induces the migration of CD301b⁺ DCs to the dLN to initiate a type 2 response in the context of allergy. This effect is mediated through MRGPRA1 rather than NK1R.³¹ Beyond DCs, SP stimulates pro-inflammatory cytokine production by human monocytes in vitro, including IL-1β secretion³² and the release of TNF and IL-6,³³ further highlighting its central role in amplifying innate immune responses. In mast cells, SP enhances activation by upregulating pattern recognition receptors.³⁴ SP also prolongs eosinophil survival and can both increase or decrease NK cell cytotoxicity in vitro.^35–37 In adaptive immunity, SP stimulates the proliferation of activated T cells either by contact with SP-secreting DCs or by directly increasing IL-2 production.^{38 39} SP contributes to T helper (Th) cell polarization, favoring a Th1-oriented response characterized by increased IFN-γ production and contributing to Th17 cell differentiation.^40–42 In B cells, SP supports immunoglobulin production.⁴³

In cancer immunity, activation of neuroimmune pathways, including SP-NK1R signaling, can significantly enhance the efficacy of radiotherapy in poorly differentiated mouse breast carcinoma. Mechanistically, SP decreases the abundance of myeloid-derived suppressor cells in both dLNs and the primary tumor while increasing CD4⁺CD25^bright T cells, which have anti-inflammatory and antitumoral effects in inflammation-driven tumor development. Moreover, SP increases the infiltration and activation of immune effector cells within the TME and boosts local production of pro-inflammatory cytokines. This leads to a more immunogenic TME that synergizes with radiation-induced tumor damage, resulting in improved tumor control (figure 1, online supplemental table).⁴⁴

Figure 1. Immunomodulatory effects of neuropeptides within the tumor microenvironment (TME). Schematic overview of the effects of major neuropeptides on immune cell populations and tumor-associated processes in the TME. Each sector summarizes the reported effects of an individual neuropeptide on immune cells. Green arrows indicate stimulation or enhancement of a process, whereas red arrows indicate inhibition or suppression. Icons at the bottom represent the immune cell populations analyzed: CD4⁺ T cells, CD8⁺ T cells, NK cells, dendritic cells (DCs), macrophages (Mac), B cells, myeloid-derived suppressor cells (MDSCs), and regulatory T cells (Treg). Figure created with BioRender.

Taken together, the effects of SP on immune cells may be either anti- or pro-tumorigenic, depending on the specific cells and tissue context. On the one hand, its capacity to enhance immune cell recruitment, activation, and cytotoxic functions can contribute to tumor control. On the other hand, if sustained over time, these same mechanisms can promote a chronic inflammatory environment that favors tumor progression. Through these actions, SP represents a key mediator linking neural signals to general immune regulation with important implications in tumor biology that still remain to be fully elucidated.

Vasoactive intestinal peptide

Vasoactive intestinal peptide (VIP) was first identified in 1968 as a 28-aa peptide encoded by the VIP gene, originally described based on its potent vasodilatory effects on blood vessels.⁴⁵ It is structurally related to the secretin/glucagon family of peptide hormones, sharing ~68% sequence identity with the pituitary adenylate cyclase-activating polypeptide.⁴⁶ VIP exerts its biological functions through two GPCRs, VIP receptor type 1 and 2 (VPAC1 and VPAC2). VPAC receptors mainly couple to Gαs, activating adenylate cyclase, increasing cAMP production, and stimulating PKA-ERK signaling.⁴⁷ VIP is produced by several cell types, including neurons of CNS and PNS. Within the PNS, it is predominantly expressed by enteric neurons of the myenteric and submucosal plexuses, although it is also produced by parasympathetic neurons and several immune cell populations.⁴⁸ In immune cells, VPAC1 is constitutively expressed on lymphocytes, macrophages, monocytes, DCs, microglia, and mast cells, while VPAC2 is induced following stimulation, especially in T cells.⁴⁹ Functionally, VIP acts as a strong anti-inflammatory factor, mediating cytokine production, cellular differentiation, and immune cell activation, and playing a key role in maintaining tissue homeostasis and preventing excessive immune responses.^{50 51} In innate immunity, VIP can suppress the production of pro-inflammatory cytokines such as TNF, IL-6, and IL-12 by macrophages, monocytes, and microglia, while promoting anti-inflammatory mediators like IL-10. In adaptive immunity, VIP directs CD4⁺ T cell differentiation from Th1 responses toward Th2 and regulatory T cell (Treg) phenotypes,⁵² contributing to immune tolerance. Additionally, VIP induces tolerogenic DCs by reducing co-stimulatory molecule expression, thereby limiting T cell activation.⁵³ Altogether, these mechanisms position VIP as a key regulator that dampens excessive inflammation and promotes an immunosuppressive, homeostatic environment across multiple immune compartments.

In the TME, VIP can originate from nerve fibers, tumor cells, and infiltrating immune cells, contributing to a complex immunosuppressive network.^{12 48} VPAC1 is the main VIP receptor studied in cancer and is overexpressed in numerous cancers, including bladder, breast, colon, liver, lung, pancreatic, prostate, thyroid, and uterus.^54–57 Activated T cells upregulate both VIP receptors,¹² and elevated VIP levels contribute to immune suppression by inducing T cell exhaustion. In agreement, combining VIP receptor antagonists with anti-PD-1 therapy improved T cell activation, attenuated exhaustion phenotypes in CD4⁺ and CD8⁺ T cells through the reduction of Tim-3⁺, PD-1⁺, and Lag3⁺ cells, promoted tumor infiltration, and led to tumor elimination and durable immunological memory in a subset of treated mice.¹² Additionally, it was shown that antagonists of VPAC1 and VPAC2 increased granzyme B and perforin expression in CD8⁺ T cells from patients with acute myeloid leukemia in vitro.⁵⁸ Beyond T cells, VIP also controlled the myeloid compartment by promoting M2-like macrophage polarization and reducing phagocytic activity, contributing to an immunosuppressive microenvironment. Blocking VIP signaling shifted macrophages toward a pro-inflammatory M1-like phenotype, enhanced tumor cell phagocytosis, and contributed to CT26 tumor control in mice.⁵⁹ Together, these findings indicate VIP signaling as a regulator of tumor-associated immune suppression, acting on both lymphoid and myeloid compartments to impair effective antitumor responses (figure 1, online supplemental table 1). Thus, blockade of the VIP-VPAC axis emerges as a promising therapeutic strategy to improve immunotherapy outcomes across multiple cancer types.

Calcitonin gene-related peptide

Calcitonin gene-related peptide (CGRP) was first identified in 1982.⁶⁰ CGRP consists of a 37-aa neuropeptide generated through alternative RNA splicing of the calcitonin gene. It has two isoforms, α-CGRP and β-CGRP, which are encoded by distinct but closely related genes (CALCA and CALCB, respectively) and display similar biological activities, although α-CGRP is the predominant form in sensory neurons.^{61 62} CGRP exerts its biological effects through the calcitonin receptor-like receptor, which requires association with receptor activity-modifying proteins (RAMPs) for full functionality. Physiologically, CGRP is mainly released by sensory neurons, and it is a potent vasodilator and a key mediator of neurogenic inflammation, promoting increased blood flow and vascular permeability. However, beyond these classical roles, CGRP exerts broad regulatory effects on immune cells in the context of pathology. CGRP-releasing neurons innervate primary and secondary immune organs, the thymus, lymph nodes, and spleen. Through binding to its receptors on multiple immune cell types, including DCs,¹⁰ macrophages,¹¹ T lymphocytes,⁶³ and NK cells,⁶⁴ CGRP generally exerts anti-inflammatory effects. This includes inhibiting DC maturation and antigen presentation,⁶⁵ shifting macrophages toward an anti-inflammatory M2-like phenotype,⁶⁶ reducing T cell proliferation and effector functions, and impairing NK cell cytotoxicity,⁶⁷ collectively contributing to a broadly immunosuppressive environment. Importantly, the immunological effects of CGRP are highly context-dependent. Outside the cancer setting, CGRP has been reported to promote IL-23 and IL-1β production by DCs and enhance Th1- or Th17-associated immune responses in specific inflammatory settings, highlighting the diverse immunomodulatory functions of CGRP.^68–70 In pathological contexts such as cancer, tumor-associated nerve fibers represent a major source of CGRP within the TME. Specifically, it was shown that CGRP can induce CD8⁺ T cell exhaustion and facilitate melanoma growth, while nociceptor ablation or RAMP1 deletion restored CD8⁺ T cell function in murine models.⁶³ Additionally, single-cell sequencing of tumor biopsies of melanoma patients revealed that RAMP1-expressing CD8⁺ T cells displayed a more exhausted phenotype than their RAMP1-negative counterparts.⁶³ A similar observation has been reported in head and neck cancer, where elevated RAMP1 expression in tumor-infiltrating CD4⁺ and CD8⁺ T cells was associated with accelerated tumor progression. Both genetic deletion of CGRP and pharmacological inhibition of its signaling pathway led to reduced tumor growth, increased T lymphocyte and NK cell infiltration, decreased expression of T cell exhaustion markers PD-1, Tim3, and Lag3, and enhanced sensitivity to radiotherapy.^{63 64 71} In medullary thyroid cancer, CGRP was shown to inhibit DC maturation by lowering CD40, CD80, CD83, CD86, and HLA-DR markers, reducing the expression of co-stimulatory molecules and impairing CD8⁺ T cell function.¹⁰ In patients with esophageal squamous cell carcinoma resistant to neoadjuvant immunotherapy, a distinct subset of RAMP1⁺ B cells exhibited an immunosuppressive profile by secreting IL-10 and TGF-β, impairing CD8⁺ T cell cytotoxic activity, and facilitating tumor immune escape. Importantly, disruption of the CGRP-RAMP1 signaling axis with RAMP1 blocker CGRP8-37 restored B cell and CD8⁺ T cell functionality and improved anti-PD-1 therapy response, representing a potential strategy to overcome therapeutic resistance.⁷² In a murine model of pancreatic ductal adenocarcinoma, nociceptive neurons interacted with cancer-associated fibroblasts via CGRP and nerve growth factor, leading to the suppression of IL-15 and reduced NK cell infiltration. This scenario favored tumor progression and exacerbated cancer-associated pain.⁶⁷ Increased nociceptive innervation correlated inversely with NK cell abundance and directly with pain severity and is associated with poorer overall and relapse-free survival.⁶⁷ Beyond established immune escape mechanisms, it has been shown that cancer cells subjected to immune pressure can activate nociceptive neurons to increase CGRP release in dLNs. This, in turn, has been proposed to reduce CCL5 production, enhance M2-like macrophage polarization, and ultimately promote tumor progression, immune evasion, and resistance to immune checkpoint blockade.¹¹ Taken together, these findings highlight CGRP as a central neuroimmune regulator that shapes tumor progression by modulating immune cell function and the TME (figure 1, online supplemental table 1), positioning the CGRP-RAMP1 axis as a promising therapeutic target to enhance antitumor immunity and overcome treatment resistance.

Neuromedin U

Neuromedin U (NMU) is a peptide of varying lengths, first discovered in the 1980s.⁷³ It is conserved across multiple species and contains a highly conserved C-terminus region. In humans, NMU is encoded by the NMU gene and is synthesized as a 174 aa-long protein, which is then cleaved into a 25 aa-long NMU peptide and one of two precursor forms, neuromedin U precursor-related peptide 33 (NURP33) or NURP36.^{73 74} To date, two high-affinity receptors for NMU belonging to the GPCR family have been identified: NMUR1 and NMUR2.^{75 76} Interestingly, the precursors, NURP33 and NURP36, do not bind to either NMUR1 or NMUR2 and their cognate receptors remain unknown.⁷⁷ NMU is expressed ubiquitously by neurons as well as immune or stromal cells, with higher levels detected in specific tissues, such as the gastrointestinal and genitourinary tracts and discrete areas of the brain.⁷⁸ In contrast, its receptors have a more restricted distribution, with NMUR1 being found in peripheral tissues, mainly gastrointestinal tract-adjacent, and NMUR2 mainly localized in the CNS.^{78 79} Mechanistically, binding of NMU to one of its receptors triggers the typical GPCR signaling cascade, resulting in activation of phospholipase C, an increase in intracellular Ca2⁺ concentration, and ultimately ERK and NFAT phosphorylation and activation.^{74 80} The first identified effect of NMU was its ability to induce smooth muscle contraction.⁷³ NMU was later described to elicit many broad effects, including regulation of blood pressure, pain perception, appetite, and energy homeostasis.^{47 73 81}

In the past decade, the focus of NMU function has slowly shifted toward the regulation of the immune system. Many immune cells show moderate expression of NMUR1, particularly type 2 innate lymphoid cells (ILC2), Th2, or cytotoxic T lymphocytes.⁹ In ILC2s, NMU stimulation is also able to increase type 2 cytokine production.⁸²

Overexpression of NMU has been detected in tumor cells across multiple cancer types, including, but not limited to, lung, pancreatic, colorectal, and breast. NMU expression is generally associated with poorer prognosis and decreased overall survival.^83–86 One of the most commonly reported effects of NMU in tumors is its ability to increase cancer cell metastatic capacity and invasiveness. Several studies described higher levels of NMU in multiple treatment-resistant cancer cells⁸³ or in tumors with higher metastatic potential.^{7 8} This aligns with observations showing that NMU overexpression or exogenous supplementation induced cell migration and dissemination, causing metastatic growth.^{84 87} Additionally, higher expression of NMU was detected in metastatic tissues in head and neck squamous cell carcinoma when compared with its expression in the primary tumor.⁸⁵ The molecular mechanism by which NMU influences the TME remains largely unclear. NMU was described to promote tumor growth by binding to growth hormone secretagogue receptor type 1 and neurotensin receptor 1, receptors structurally related to NMUR1 and NMUR2, making the identification of the underlying mechanism more difficult.⁸⁷ It has been proposed that NMU supports epithelial-mesenchymal transition and promotes cancer cell stemness by inducing glycolysis.⁸⁸ Similarly, hypoxia was indicated as a factor capable of upregulating NMU expression,⁸⁹ which may at least in part explain the NMU positive feedback loop observed in many cancers.^{87 90} Additionally, co-expression analysis of tumor datasets showed that NMU is expressed alongside genes associated with type 2 immune responses and immune suppression, such as IL4, IL13, FOXP3, and IL10.⁹¹ This is further supported by previous observations of positive association between NMU expression and the proportion of type 2 macrophages in the TME,⁸⁶ in turn contributing to an increased migratory potential of cancer cells.⁵ In addition, NMU stimulation reduces the cytotoxic ability of CD8⁺ T cells, most likely through glycolysis-related processes.⁹² One study shows some promise in the therapeutic potential of NMU inhibition for overcoming treatment resistance in HER2-overexpressing breast cancer cells.⁸³ However, research on therapeutic applications of NMU inhibitors or antagonists is largely missing (figure 1, online supplemental table 1).

Taken together, NMU is produced by cancer cells, which causes the induction of suppressive immune signatures, leading to increased cancer cell migration and ultimately resulting in metastasis. On this basis, NMU and its receptors are considered poor prognosis markers in all examined types of cancer.

Neuropeptide Y

Neuropeptide Y (NPY) is a 36-aa-long peptide first identified in the 1980s.⁹³ In humans, it is encoded by the NPY gene and expressed primarily in the neurons of the CNS with sparse peripheral expression.^{94 95} NPY is cleaved from a 97 aa-long pro-peptide along with a 30 aa-long C-terminal flanking peptide of neuropeptide Y (CPON). Despite being stored and released alongside NPY, no biological function of CPON has been recorded.⁹⁶ NPY is structurally closely related to peptide YY and pancreatic polypeptide, both present along the gastrointestinal tract. Even though NPY was the last of these to be identified, it seems to have arisen earlier in evolution, as it is conserved across phylogenetically older taxa.⁹⁷ All three peptides are involved in appetite regulation, energy homeostasis, and stress response.^{93 98–100} In humans, four functional receptors for NPY have been identified: NPY1R, NPY2R, NPY4R, and NPY5R (NPY3R was later reclassified as CXCR4 and NPY6R is an inactive receptor).^101–103 All NPY family peptides bind to all receptors with varying affinities, depending on the specific peptide-receptor combination.⁹⁷ The receptors are expressed broadly across the body, with NPY1R and NPY2R being present predominantly in the CNS.¹⁰⁴

Given the angiogenic properties of NPY and its elevated levels in cancer tissues, its role in the TME has become the focus of many studies.^105–107 Indeed, both NPY and its receptors seem to be locally upregulated across multiple types of cancer.^{107 108} Most studies report increased metastatic potential in tumors with high NPY expression.^109–111 This is further supported by reduced liver metastases in a pancreatic cancer model lacking NPY1R.¹¹² However, the literature is inconsistent regarding the receptor responsible for NPY effects, and the underlying mechanism remains ill-defined. Several studies proposed that TGF-β triggers NPY and NPY receptor expression in cancer-adjacent cells, promoting cancer cell migration and invasion.^113–115 In the TME, NPY may also suppress the antitumor function of immune cells. NPY has been shown to inhibit proliferation of T cells by interfering with IL-2 release and indirectly promoting differentiation toward a more pro-resolution type 2 phenotype.^{116 117} NPY can also mediate infiltration of myeloid cells, mainly macrophages, and their accumulation in the tumor.¹¹⁸ Additionally, it can reduce macrophage phagocytosis and impair phagosome maturation.^{119 120} NPY appears to influence NK cells, although the reported studies are contradictory. While an early in vitro study suggested that NPY can suppress cytotoxic activity of NK cells, a later report described a completely opposite effect (figure 1, online supplemental table 1).^{116 121}

In general, high NPY expression is associated with poorer prognosis and an increased risk of metastasis. It can promote tumor vascularization and tumor cell extravasation. Additionally, NPY can act as a chemotactic agent to recruit myeloid cells to tumors, contributing to the formation of an immunosuppressive environment. While targeting NPY holds therapeutic potential, such strategies should be approached with caution due to limited data and varying results and context-dependent effects.

Conclusion

High levels of tumor innervation are associated with poorer patient prognosis and reduced relapse-free survival.¹²² Within tumors, peripheral neurons secrete neurotransmitters and neuropeptides to communicate and regulate their local environment. While neurotransmitters primarily act over short distances between nearby cells, neuropeptides can diffuse more broadly through tissues due to their small size and longer half-life.¹²³

To date, more than a hundred neuropeptides have been identified. They function to maintain homeostasis and regulate metabolism.¹²⁴ Despite their diversity and often very localized expression, the knowledge of their influence on the immune system is limited. Here, we summarize key neuropeptides involved in the regulation of immune cells in cancer. One of the most prominent effects of neuropeptides in the TME is their ability to promote angiogenesis. In healthy tissues, this process is essential for supplying neurons with sufficient nutrition and oxygen. However, tumor cells can hijack this mechanism by producing neuropeptides to secure their own nutrient supply. Another important effect of tumor-derived neuropeptides is the recruitment of immune cells. Under physiological conditions, neuropeptides contribute to immune regulation by limiting excessive inflammation, reducing pro-inflammatory cytokine release, and promoting resolving immune phenotypes. In tumors, these same mechanisms can reinforce an immunosuppressive environment, which supports tumor progression. Increased neuropeptide production by cancer cells has been shown to not only induce recruitment of immune cells but also to support epithelial-mesenchymal transition in tumor cells, a key process contributing to metastasis. As a result, high neuropeptide levels in primary tumors or in circulation may serve as potential prognostic markers and help guide treatment decisions. Furthermore, disruption of neuropeptide signaling is showing some promise as an adjunct to standard anti-cancer therapies and may help overcome treatment resistance. Overall, the majority of studied neuropeptides exert predominantly pro-tumorigenic effects. Nevertheless, the effects of SP on immune cell recruitment, activation, and cytotoxicity suggest that it can also promote antitumoral functions depending on the immune and tissue context.

However, current data remain limited, with only a handful of studies examining multiple neuropeptides in the context of cancer. Altogether, further investigation into neuropeptide signaling is warranted. Improved understanding and detection could enhance predictions of disease progression, while therapeutic modulation of these pathways may increase treatment efficacy. Focusing on neuropeptides in cancer therefore holds promise for advancing more personalized and effective therapeutic strategies.