Extended Data Fig. 12: Melanoma-innervating nociceptors attenuate cancer immunosurveillance.

Melanoma growth sets off anti-tumour immune responses, including the infiltration of effector CD8 T cells and their subsequent release of cytotoxic cytokines (i.e., IFNγ, TNF, Granzyme B). By acting on tissue-resident nociceptor neurons, melanoma-produced SLPI promotes pain hypersensitivity, tweaks the neurons’ transcriptome, and drives neurite outgrowth. These effects culminate in dense melanoma innervation by nociceptors and abundant release of immunomodulatory neuropeptides. CGRP, one such peptide, acts on tumour-infiltrating effector CD8⁺ T cells that express the CGRP receptor RAMP1, increasing their expression of immune checkpoint receptors (i.e., PD-1, LAG3, TIM3). Therefore, along with the immunosuppressive environment present in the tumour, nociceptor-produced CGRP leads to the functional exhaustion of tumour-infiltrating CD8⁺ T cells, which opens the door to unchecked proliferation of melanoma cells. Genetically ablating (i.e., TRPV1 lineage) or pharmacologically silencing (i.e., QX-314, BoNT/A) nociceptor neurons as well as blocking the action of CGRP on RAMP1 using a selective antagonist (i.e., BIBN4096) prevents effector CD8⁺ T cells from undergoing exhaustion. Therefore, targeting melanoma-innervating nociceptor neurons constitutes a novel strategy to safeguard host anti-tumour immunity and stop tumour growth.