Melanoma, an aggressive skin cancer, often evades even today’s best immunotherapies. A surprising contributor is the nervous system. Tumors grow new nerve fibers and “talk” with nearby pain‑sensing neurons (nociceptors). When these nerves are active, they can release substances that blunt T‑cell attack and help cancer progress. Our work suggests that there is a built-in way to quiet these nerves and re-empower the immune system.

We discovered that a sizable subset of B cells within melanoma produces nociceptin, a natural paindampening molecule. Patients whose tumors exhibit higher levels of the nociceptin gene (PNOC) or its receptor (OPRL1, also known as NOP) tend to have longer survival times. In human melanoma single-cell data, PNOC is specifically found in tumor-infiltrating B cells. In mouse models, tumor‑innervating nociceptors increase OPRL1, making them responsive to B‑cell‑derived nociceptin. Turning this pathway on with nociceptin reduced pain, slowed tumor growth, and boosted tumor‑killing T cells; blocking it had the opposite effects and depended on B cells. Together, these findings identify a nerve–immune circuit that can be activated or deactivated.

We will test the hypothesis that B-cell-produced nociceptin restrains melanoma by silencing tumorinnervating nociceptors. 1 will define how nociceptin alters tumor nerves and pain signaling using mice engineered to remove PNOC only from B cells and neuron–tumor co‑cultures. 2 will measure how this neural quieting reshapes the tumor’s immune makeup, focusing on T‑cell function and myeloid cells. 3 will evaluate NOP‑targeted drugs together with anti‑PD‑1 therapy to see if engaging this circuit improves response.

Impact: This project reframes tumor nerves as actionable partners in cancer control. If successful, it could lead to two immediate strategies: using nociceptin-like agents to calm peripheral sensory neurons and repurposing approved anti-migraine drugs that block pro-tumor nerve signals. The goal is better tumor control with less pain and suffering for patients everywhere.