Over the past decade, there has been a surge of interest in understanding the role of sympathetic nerves in promoting tumor growth and driving immunosuppression. Molecular analyses are confirming older observations from the field of psychoneuroimmunology which indicated that nervous stimulation could suppress immune responses and accelerate tumor progression.1 But how do tumors acquire the immunosuppressive complement of nerves? Recent studies revealed that tumors release nerve-attracting secretions, including nerve growth factor (NGF). NGF plays a crucial role in the normal growth, survival, and maintenance of neurons in both the peripheral and central nervous systems, contributing to learning and memory. Additionally, NGF influences immune responses, wound healing, and tissue regeneration by modulating inflammation and cell proliferation.2 3 In cancer, NGF drives sympathetic nerve recruitment and expansion. In turn, the increased sympathetic neurotransmitter accumulation contributes to immunosuppression and poor cancer prognosis by reducing T-cell infiltration and promoting M2 macrophages and T regulatory cells in the tumor microenvironment (TME).4–7

Building on these foundational discoveries, Yang et al 8 now demonstrate how we may be able to target tumor-produced NGF to block tumor growth and re-stimulate antitumor immunity. These researchers tested the hypothesis that engineering CAR T cells to produce an anti-NGF single-chain antibody in the TME can effectively decrease catecholamine levels by blocking tumor innervation and mitigating its impact on immune cells within the TME. More specifically, in the setting of clear cell renal cell carcinoma, they engineered NGF single-chain variable fragment (scFv)-secreting CAR T to counteract the effects of NGF and confirmed that these NGF scFv effectively inhibits NGF binding to its receptor, tropomyosin receptor kinase A (TrkA). They developed a chimeric antigen receptor (CAR) T cell that targets the cells to vascular endothelial growth factor receptor 2 (VEGFR2) (named V28z) and V28z/αNGF CAR T cells that produce anti-NGF scFv. They tested these against cell lines in vitro and both CAR T cells exhibited comparable cytotoxic effects in bEnd.3 and MS1 cell lines in vitro, with no toxicity observed in Rena cells, used as a negative control. However, V28z/αNGF displayed significantly enhanced antitumor efficacy in mouse models compared with V28z CAR T cells.8

Further analyses revealed that NGF blockade reduced sympathetic nerve innervation in tumors, as evidenced by decreased levels of epinephrine and norepinephrine and reduction in the presence of nerves in the tumor. This blockade altered the immune contexture of the TME by increasing infiltration of CD3+ T cells and CAR+ T cells. Phenotypically, by reducing the sympathetic component of the TME and the associated release of catecholamines, NGF scFv decreased T-cell exhaustion, particularly numbers of terminally exhausted T cells, and reduced the accumulation of M2-like macrophages. Additionally, NGF scFv enhanced the effector function of splenic T cells, indicating its systemic impact on antitumor immunity alongside its role in modulating the TME (figure 1).

NGF blockade reverses sympathetic nerve-mediated immunosuppression in the TME. Schematic illustration of the impact of the sympathetic nervous system on the immune response within the TME. NGF released by tumor cells promotes sympathetic nerve innervation of the tumor. Catecholamines released by sympathetic nerves induce the accumulation of M2 macrophages and Tregs while suppressing antitumor CD8+ T cells. Secretion of anti-NGF scFv by CART cells reduces intratumoral catecholamine levels, leading to a decrease in immunosuppressive cells and an increase in antitumor cells, including IFN-γ+ CD8+ T cells and M1 macrophages. CAR, chimeric antigen receptor; IFN-γ, interferon-gamma; M1 type 1-like macrophages; M2 type 2-like macrophages; NGF, nerve growth factor; scFv, single-chain variable fragment; TME, tumor necrosis factor; Treg, regulatory T cells; TrkA, tropomyosin receptor kinase A.

These findings align with prior studies showing that sympathetic nerve blockade enhances the efficacy of antitumor T cells locally and systemically through various pathways such as neural substance P9 10 and beta-adrenergic receptor (β-AR) signaling.11–20 Collectively, the data provide a compelling rationale for targeting biological mechanisms tied to tumor growth to enhance cellular therapies, such as CAR T cells and tumor-infiltrating lymphocytes.21

These results are also in accordance with previous research indicating that targeting the NGF-TrkA pathway in tumor cells can reduce tumor growth and stimulate an antitumor immune response in prostate and breast cancers.22 In breast cancer, this pathway plays a crucial role in enhancing resistance to apoptosis, promoting cancer cell proliferation, and facilitating invasion.23–25 Similarly, in prostate cancer cells expressing the TrkA receptor, the NGF-TrkA pathway drives proliferation, invasiveness, and epithelial-mesenchymal transition in various castration-resistant prostate cancer cells, while specific TrkA inhibition effectively disrupts these processes.26 27 Collectively, these findings reinforce the rationale for targeting the NGF-TrkA pathway with pharmacological inhibitors or CAR T-cell therapy, as well as exploring novel strategies such as targeting β2-AR in T cells28 to counteract the suppressive effects of the sympathetic nervous system on T cell-mediated antitumor responses, ultimately promoting tumor regression. However, further studies are needed to assess clinical potential and the possible side effects of long-term NGF blockade, including unintended CAR T-cell accumulation in non-tumor sites and exposure of normal tissues to scFv, given NGF’s critical role in nerve maintenance, repair, and nervous system homeostasis.

These exciting new data should also remind researchers in this field of the observations made over 80 years ago by Rita Levi-Montalcini and her colleagues. It has been largely overlooked during the intervening years that it was the implantation of a mouse tumor (sarcoma) into the chick embryo that spurred nerve outgrowth into the tumor, revealing the existence of NGF, for which the Nobel Prize was awarded to Drs Levi-Montalcini and Stanley Cohen in 1986.29 With the discoveries being made in rapid fashion over just the past decade demonstrating the ability of these NGF-recruited nerves to ensure tumor survival against the immune system, combined with the exciting new therapeutic potential identified by Yang et al,8 we should be all the more aware of the importance of early research in this field and the events which shaped modern nerve-tumor-immunity axis. Indeed, a comment by Dr Levi-Montalcini that “The entire history of nerve growth factor can be compared to the discovery of a sunken continent revealed by its emerging top” truly reflects that we are only just beginning to understand the critical role of nerves and NGF in tumor progression and their potential as therapeutic targets.30