As mentioned above, autonomic neural signals can not only affect tumor cells but also other types of cells, especially immune cells. The inflammatory status in the body is regulated via humoral and neuronal pathways [105,106,107].

Associations between neuronal and immune systems have been reported to influence tumor immunity [109,110]. Neurogenic signatures were shown to be associated with immunosuppressive phenotypes [111].

The function of T cells, especially cytotoxic CD8⁺ T cells, is critical for anti-tumor immunity [112]. Some studies have suggested that neural signaling plays a role in controlling anti-tumor T cell functions. The ablation of sympathetic nerves decreased programmed death-1 (PD-1) and FOXP3 expression on T cells in breast cancer [29]. Accordingly, the parasympathetic stimulation of breast cancer cells decreased PD-L1 expression on tumor cells and PD-1 on T cells and increased CD8⁺/regulatory T (Treg) cells [29]. Another study demonstrated that the inhibition of β2-adrenergic receptor signaling on immune cells led to increased CD8⁺ T cells and decreased PD-1 expression on T cells [55]. In prostate cancer, PD-L1 expression on nerves in the tumor microenvironment was inversely correlated with the prevalence of CD8⁺ T cells and patient prognosis [113].

Macrophages infiltrating the tumor microenvironment are called tumor-associated macrophages (TAMs), which exert various effects to promote tumor initiation and progression [114]. In breast cancer, β-adrenergic nerve stimulation induces infiltration and the differentiation of tumor-promoting macrophages in the tumor microenvironment, leading to tumor progression and angiogenesis [56]. In contrast, cholinergic signaling suppresses the CD11b⁺ myeloid cell population and TNFα expression in the PDAC microenvironment, indicating the tumor suppressive and anti-inflammatory effect of cholinergic signaling [40]. Macrophages in the PDAC microenvironment are recruited by C-C chemokine receptor type 2 (CCR2) and colony-stimulating factors and secrete GDNFs to promote cancer migration and nerve invasion [115].

Myeloid-derived suppressor cells (MDSCs) are activated neutrophils and monocytes which have immune suppressive functions to promote tumor progression [116]. In melanoma, inhibition of β3-adrenergic receptor signaling attenuated regulatory T cells and MDSC increased the number and cytotoxicity of natural killer (NK) cells and increased the ratio of M1/M2 macrophages and N1 granulocytes [57]. Sensory neurons have been reported to secrete several CCL and CXCL chemokines in the melanoma microenvironment, attracting MDSCs to promote immune-tolerant conditions [82]. In colon cancer, cholinergic stimulation prevents colon cancer progression by inducing anti-inflammatory peptide trefoil factor 2 secretion from memory T cells to suppress MDSC expansion [74].

NK cells also play an important role in innate tumor immunity [117]. NK cells and nerves interact in the context of the degeneration of damaged sensory neurons through the NK cell receptor NKG2D and retinoic acid early-inducible 1 (RAE1) gene [118]. Due to β2 adrenergic receptor signaling, NK cells and other leukocytes are mobilized into circulation [119].

Eosinophils are granulocytes involved in innate immunity and have been shown to interact with neurons [120]. Nerves recruit eosinophils through the stimulation of neuropeptides, cytokines, and chemokines; eosinophils release cationic proteins, neurotrophins/neuropeptides, and ROS to induce nerve growth and neuropeptide synthesis. In the tumor microenvironment, the role of eosinophils seems to be context-dependent [121]. In some cancers, including melanoma, eosinophils exhibit anti-tumorigenic roles in mouse models, suggesting a novel therapeutic strategy.

Angiogenesis during tumor development has also been reported to be promoted by neural inputs. Vascular organization during development has been shown to be affected by sensory neurons [122], as well as signaling via neuropeptide Y [123]. In the tumor microenvironment, sympathetic nerve signaling induces angiogenesis, and TECs, in turn, promote tumorigenesis by secreting cytokines and growth factors [58]. Systemic sympathetic nerve stimulation by the chronic restrain model revealed increased vascular endothelial growth factor (VEGF) expression and angiogenesis via β2-adrenergic receptor signaling in ovarian tumor cells [14]. Catecholamines signaling through β-adrenergic receptors also induced expression of VEGF and IL-6 in breast cancer cells [59]. In prostate cancer, β2-adrenergic receptor signaling on endothelial cells promoted tumor angiogenesis and tumor progression [13], suggesting a mechanism involving immune regulation by sympathetic nerves through endothelial cells. In addition, catecholamine treatment induced the alternatively activated M2 polarization of macrophages to secrete VEGF and promote tumor angiogenesis in a lung cancer mouse model [124]. On the other hand, dopamine, a neurotransmitter of sympathetic nerves, downregulates VEGF receptor 2 signaling in endothelial cells [62] and inhibits colon cancer angiogenesis and growth [63]. Similarly, gastric cancer and ovarian cancer mouse models have shown decreased tumor angiogenesis and tumor growth after dopamine treatment [64,65]. Collectively, in the tumor microenvironment, sympathetic innervation promotes angiogenesis supporting tumor progression.

CAFs are key components in the tumor microenvironment and have been extensively investigated and shown to have various functions, including modifying matrix deposition, reciprocal signaling, and interacting with cancer cells and immune cells to promote cancer progression [125]. CAFs have also been shown to secrete several axon-guidance molecules. Exosomes derived from head and neck cancer cells induced NGF expression in fibroblasts [126]. Pancreatic stellate cells also produce neurotrophic factors NGFs and artemin in response to transforming growth factor β (TGF-β) to induce neurite outgrowth [127,128,129]. In pancreatic cancer, CAFs expressing NetrinG1, an axon-guidance molecule, have been shown to metabolically support tumor growth by affecting glutamate/glutamine metabolism and inhibiting NK-cell-mediated tumor killing via the Akt and p38 pathways [130]. CAFs in the pancreatic cancer microenvironment have been reported to secrete an axon guidance molecule, SLIT2, to induce neural outgrowth [131]. These studies suggest that CAFs are an important mediator of tumor innervation and neural remodeling in the tumor microenvironment.

In adipocytes, β-adrenergic signaling, especially β3, is involved in the lipolytic mobilization of fatty acids [132,133]. In the cancer microenvironment, CAAs have been reported to promote tumor growth, angiogenesis, and migration through the secretion of hormones, cytokines, adipokines, and growth factors [134].

The mechanism of how neural cells expand in the tumor microenvironment is not clearly understood. One possibility is that pre-existing nerves directly innervate from the surrounding tissue. Co-culturing neural ganglia and cancer cells promote neurite outgrowth [38,39]. Such innervation might be induced by neurotrophins including nerve growth factors. Another possibility is the trans-differentiation of cells in the tumor microenvironment. Amit and colleagues reported that loss of TP53 in oral cancer induced the trans-differentiation of tumor-associated sensory neurons into adrenergic neurons [34]. Another study suggested the possibility of the trans-differentiation of cancer cells into neural cells in the tumor microenvironment of prostate cancer [135]. Lastly, neural progenitor cells might be recruited to the tumor microenvironment from distant organs. Mauffrey and colleagues reported that doublecortin (DCX)-positive neural progenitors from the central nervous system infiltrated prostate primary tumors and metastases [136].

Various molecules, including neurotrophins, axon guidance molecules, and cytokines, are reportedly involved in the development and function of nerves in the tumor microenvironment (Figure 3).