Prehabilitation as a Strategy to Modulate the Tumor Microenvironment in Pancreatic Cancer

Multimodal prehabilitation aims to enhance resilience to cancer therapy through exercise, nutrition, and psychological optimization. While prehabilitation can improve physical condition and functional status, its biologic influence on the tumor microenvironment (TME) remains poorly characterized. In pancreatic ductal adenocarcinoma (PDAC), the TME is dominated by immunosuppressive and desmoplastic features that limit immune cell infiltration and therapeutic efficacy. As an exploratory pilot analysis, this study characterized the cellular composition, spatial relationships, and functional signaling of the pancreatic TME in patients who underwent prehabilitation prior to surgical resection and those who did not. Tumor samples from eight patients (four prehabilitation, four control) were analyzed with a 34-plex protein panel using Imaging Mass Cytometry (IMC), categorizing the tumor-immune landscape and functional status at the single-cell resolution. Prehabilitation tumors demonstrated reduced neutrophil and epithelial/tumor cell density and enrichment of Natural Killer (NK), CD4⁺, and CD8⁺ T cells. Spatial analysis revealed an immune-permissive architecture in prehabilitation tumors, in contrast to immune-resistant patterns in controls. Functional marker analysis showed reduced activation and pro-tumor signaling in immunosuppressive populations, including Tregs (HLADR, pAkt, pNFκB) and Collagen⁺ CAFs (NOS2, pERK, pNFκB, pSTAT3). These preliminary findings raise the possibility that prehabilitation is associated with an immune-permissive TME in PDAC, supporting further investigation of its immunomodulatory potential in larger, prospectively designed cohorts.