CGRP–RAMP1/CALCRL Signaling Drives TGF-β2-Mediated Immune Evasion and Pancreatic Cancer Progression

Pancreatic ductal adenocarcinoma (PDAC) is characterized by extensive neural remodeling and a profoundly immunosuppressive tumor microenvironment, both of which contribute to disease progression and therapeutic resistance. However, whether nociceptor-derived signals directly reprogram PDAC cells to promote immune evasion remains poorly understood. Here, we identify a previously unrecognized tumor-intrinsic neuroimmune mechanism driven by calcitonin gene-related peptide (CGRP) signaling through the receptor complex RAMP1/CALCRL on PDAC cells. CRISPR/Cas9-mediated deletion of Ramp1 or Calcrl did not alter PDAC cell proliferation in vitro but markedly suppressed tumor growth and prolonged survival in immunocompetent mice. These antitumor effects were lost in immunodeficient hosts, indicating that the pro-tumorigenic function of CGRP signaling depends on an intact host immune system. Consistently, tumor cell-specific loss of Ramp1 or Calcrl remodeled the tumor immune microenvironment, enhancing CD4+ and CD8+ T-cell effector activity. Mechanistically, CGRP stimulation promoted TGF-β2 expression and secretion by PDAC cells in a RAMP1-dependent manner. Tumor-derived TGF-β2 subsequently acted in a paracrine fashion to suppress CD8+ T-cell activation and cytotoxic function, whereas genetic disruption of RAMP1 or pharmacological inhibition of TGF-β signaling relieved this immunosuppression. Together, these findings define a CGRP–RAMP1/CALCRL–TGF-β2 signaling axis through which nociceptive input is converted into tumor-driven adaptive immune evasion in PDAC. This pathway reveals a previously underappreciated mechanism linking neural signaling to PDAC progression and identifies CGRP receptor signaling as a potential therapeutic vulnerability for restoring antitumor immunity and improving the responsiveness of PDAC to immunotherapy.