CALCA and melanoma: Pharmacologic blockade of RAMP1 or knockout of the transient receptor potential vanilloid 1 (TRPV1, a sensory neuron ion channel) caused a reduction of CGRP+ signaling in TME, leading to decreased T cell exhaustion, reduced cancer size, as well as extended overall survival rates.127 ScRNA-seq of human melanoma tissues illuminated that RAMP1+ CD8+ T cell exhibited higher levels of exhaustion compared to RAMP1− CD8+ T cells, and patients with higher intensity of RAMP1+ CD8+ T cells had poorer survival rates127 (Fig. 4).