Changing Course: Semaphorins and Plexins as Novel Therapeutic Opportunities and Key Regulators of Pancreatic Cancer Microenvironment
- 1Tumor Microenvironment Laboratory, INOC—Istituto Nazionale Oncologico Candiolo, IRCCS, 10060 Candiolo, Turin, Italy
- 2Department of Science and Drug Technology, University of Turin, 10125 Turin, Italy
Abstract
Pancreatic ductal adenocarcinoma (PDAC) remains one of the deadliest solid tumors, and despite recent advances in surgical and systemic therapies, outcomes remain poor, rooted as much in the genetic mutations that initiate the disease as in a fibrotic, poorly vascularized microenvironment marked by scarce immune infiltration and a dense network of nerve fibers. Semaphorins, together with their receptors plexins and co-receptors neuropilins, have emerged as pivotal orchestrators of this microenvironment, shaping crosstalk between malignant cells, fibroblasts, macrophages, the endothelium, and peripheral neurons. This review examines how individual semaphorin family members drive, or in select contexts restrain, stromal activation, immune exclusion, pathological angiogenesis and neural remodeling. Building on this mechanistic framework, we explore the clinical relevance that semaphorin-mediated signaling holds for PDAC, from its potential as a prognostic and predictive biomarker to its growing promise as a therapeutic target, positioning this axis as a compelling frontier for improving outcomes in a disease that has long resisted meaningful therapeutic advances.
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BibTeX
@article{bertalmio2026changing,
title = {{Changing Course: Semaphorins and Plexins as Novel Therapeutic Opportunities and Key Regulators of Pancreatic Cancer Microenvironment}},
author = {Nicolò Bertalmio and Francesca Anna Lourdes Marino and Serena Brundu and Serena Rustichelli and Enrico Giraudo},
journal = {International Journal of Molecular Sciences},
year = {2026},
month = oct,
doi = {10.3390/ijms27219788},
url = {https://www.mdpi.com/1422-0067/27/21/9788},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Changing Course: Semaphorins and Plexins as Novel Therapeutic Opportunities and Key Regulators of Pancreatic Cancer Microenvironment
AU - Nicolò Bertalmio
AU - Francesca Anna Lourdes Marino
AU - Serena Brundu
AU - Serena Rustichelli
AU - Enrico Giraudo
PY - 2026
DA - 2026/10/31
JO - International Journal of Molecular Sciences
DO - 10.3390/ijms27219788
UR - https://www.mdpi.com/1422-0067/27/21/9788
AB - Pancreatic ductal adenocarcinoma (PDAC) remains one of the deadliest solid tumors, and despite recent advances in surgical and systemic therapies, outcomes remain poor, rooted as much in the genetic mutations that initiate the disease as in a fibrotic, poorly vascularized microenvironment marked by scarce immune infiltration and a dense network of nerve fibers. Semaphorins, together with their receptors plexins and co-receptors neuropilins, have emerged as pivotal orchestrators of this microenvironment, shaping crosstalk between malignant cells, fibroblasts, macrophages, the endothelium, and peripheral neurons. This review examines how individual semaphorin family members drive, or in select contexts restrain, stromal activation, immune exclusion, pathological angiogenesis and neural remodeling. Building on this mechanistic framework, we explore the clinical relevance that semaphorin-mediated signaling holds for PDAC, from its potential as a prognostic and predictive biomarker to its growing promise as a therapeutic target, positioning this axis as a compelling frontier for improving outcomes in a disease that has long resisted meaningful therapeutic advances.
SN - 1422-0067
ER -