CGRP–RAMP1/CALCRL Signaling Drives TGF-β2-Mediated Immune Evasion and Pancreatic Cancer Progression
- 1Nanhu Laboratory, State Key Laboratory of Biomedical Analysis (SKLBA, Formerly Known as National Center of Biomedical Analysis), Beijing 100039, China
- 2School of Basic Medical Sciences, Fudan University, Shanghai 200032, China
Abstract
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.
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BibTeX
@article{zhang2026cgrpramp1calcrl,
title = {{CGRP–RAMP1/CALCRL Signaling Drives TGF-β2-Mediated Immune Evasion and Pancreatic Cancer Progression}},
author = {Biyu Zhang and Yaxin Li and Simiao Fan and Jiamei Zhang and Yu Zhang and Wen Wang and Liang Luo and Wanying Xiao and Xinlei Xie and Xiaoxiao Jian and Qiuying Han and Shaoyi Huang and Min Wu and Zengqing Song and Yuqi Wen and Haiqing Tu and Sen Li and Huaibin Hu},
journal = {International Journal of Molecular Sciences},
year = {2026},
month = oct,
doi = {10.3390/ijms27209108},
url = {https://www.mdpi.com/1422-0067/27/20/9108},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - CGRP–RAMP1/CALCRL Signaling Drives TGF-β2-Mediated Immune Evasion and Pancreatic Cancer Progression
AU - Biyu Zhang
AU - Yaxin Li
AU - Simiao Fan
AU - Jiamei Zhang
AU - Yu Zhang
AU - Wen Wang
AU - Liang Luo
AU - Wanying Xiao
AU - Xinlei Xie
AU - Xiaoxiao Jian
AU - Qiuying Han
AU - Shaoyi Huang
AU - Min Wu
AU - Zengqing Song
AU - Yuqi Wen
AU - Haiqing Tu
AU - Sen Li
AU - Huaibin Hu
PY - 2026
DA - 2026/10/01
JO - International Journal of Molecular Sciences
DO - 10.3390/ijms27209108
UR - https://www.mdpi.com/1422-0067/27/20/9108
AB - 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.
SN - 1422-0067
ER -