Neuropeptide Y as a Neuro-Immune Checkpoint in Cancer.

Neuropeptide Y (NPY) is a highly conserved 36-amino acid neuropeptide broadly distributed throughout the central and peripheral nervous systems, where it classically regulates appetite, stress responses, and circadian rhythms. Increasing evidence now positions NPY as a critical mediator at the interface of neural and immune signaling within the tumor microenvironment (TME). In cancer, NPY is released not only from tumor-innervating sympathetic fibers but also, in some contexts, directly from tumor cells, thereby establishing autocrine and paracrine signaling circuits that support tumor progression. Acting through its G protein-coupled receptors (Y1, Y2, Y4, Y5, and Y6), NPY exerts pleiotropic effects on both malignant and immune cell populations. Activation of Y1R and Y2R has been associated with enhanced tumor cell proliferation, angiogenesis, and vascular remodeling, whereas Y5R links stress-associated neuroendocrine signaling to accelerated tumor growth. Importantly, within the immune compartment, NPY promotes macrophage polarization toward an M2-like immunosuppressive phenotype, suppresses natural killer cell cytotoxicity, and dampens T cell activation, collectively fostering a tolerogenic and immune-evasive TME. These convergent neural and immunological effects highlight NPY as a dual-function neuromodulator and immunoregulator in cancer. In this review, we propose that NPY signaling represents a previously underappreciated neuro-immune checkpoint that integrates stress signals with tumor immune suppression. Targeting the NPY-receptor axis may therefore offer novel opportunities to reprogram the neuro-immune landscape of tumors and enhance the efficacy of cancer immunotherapy, particularly in stress-responsive malignancies.