Prehabilitation as a Biologically Active Intervention Is Associated with the Remodeling of the Pancreatic Tumor-Immune Microenvironment

TL;DR

Prehabilitation before surgery may improve the immune environment in pancreatic cancer, potentially leading to better survival.

Contribution

This study shows prehabilitation remodels the tumor-immune microenvironment in pancreatic cancer patients.

Findings

Prehabilitation increased NK-cell cytotoxicity and interferon response in the tumor microenvironment.

Neutrophil-high/fibroblast-low profiles were linked to longer survival in pancreatic cancer patients.

Tumor regions showed reduced MAPK and PI3K/AKT activity after prehabilitation.

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is highly lethal, and many patients cannot undergo curative surgery due to frailty. Multimodal prehabilitation: combining exercise, nutrition, and psychological support improves functional readiness, but its biological impact on the PDAC tumor microenvironment (TME) is unclear. In this exploratory pilot study, we profiled resected PDAC tissues from prehabilitation-treated patients and matched controls using NanoString GeoMx Digital Spatial Profiling across immune, tumor, and stromal compartments (n = 4). Transcriptomic signatures were analyzed via differential expression, pathway enrichment, and MCP-counter deconvolution; protein-level validation used multiplex immunofluorescence (n = 8). Ligand–receptor modeling assessed cell–cell communication, and prognostic relevance was evaluated in TCGA-PDAC (n = 178). Prehabilitation was associated with increased NK-cell cytotoxicity, interferon response, and chemokine recruitment, as well as higher neutrophil signatures (p < 0.01) and reduced fibroblast signatures (p < 0.05). Tumor regions showed lower MAPK and PI3K/AKT activity, while stroma exhibited decreased TGF-β and Wnt signaling. Immunofluorescence confirmed neutrophil infiltration and reduced fibroblast density. TCGA analysis linked neutrophil-high/fibroblast-low profiles to longer survival (1044.6 vs. 458.7 days, p = 0.0052). These findings suggest prehabilitation may promote a more immune-active, less fibrotic TME in PDAC, resembling transcriptional states associated with improved survival. Prospective studies integrating biological and clinical endpoints are warranted.

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