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.

Background/Objectives: Through survey and analysis of pancreas cancer patient–caregiver dyads, we aimed to identify patient and caregiver characteristics that influence and determine the impact of caregiver coping strategies, self-esteem, and resilience on caregiver distress. Methods: This was a cross-sectional, observational study including pancreatic cancer patients and their caregivers. Demographics of patients and caregivers were collected. Caregivers completed validated instruments (National Comprehensive Cancer Network (NCCN) Distress Thermometer, Caregiver Reaction Assessment (CRA), Perceived Stress Scale 4 (PSS-4), Patient Reported Outcomes Measurement Information System-Anxiety/Depression Short Form (PROMIS-Anxiety/Depression), Brief Resilience Scale (BRS), Zarit Caregiver Burden Interview (CBI-12), and Brief Coping Orientation to Problems Experienced (COPE)) investigating anxiety, depression, perceived stress, caregiver burden, use of approach and avoidant coping, resilience, and self-esteem. Descriptive statistics, univariate, and multiple linear regression models were used to analyze the data. Results: One hundred and fourteen patient–caregiver dyads were included in this study. The majority of patients were male (55%), 65% of caregivers were female, and 64% of patients were receiving palliative intent treatment. Younger caregiver age, more personal care tasks, higher patient distress, and caregiving for a parent were characteristics related to caregiver avoidant coping. Fewer caregiving activities and early clinical stage were associated with caregiver approach coping. High caregivers’ self-esteem was significantly associated with fewer personal care tasks to perform and with caregivers of patients with higher levels of education. Avoidant coping and low resilience were both significantly correlated to distress, anxiety, depression, caregiver burden, and perceived stress. Additionally, low self-esteem was associated with a high perceived caregiver burden. Conclusions: Overall, caregiver factors such as age, relationship with the patient, and number of care tasks and activities influence caregivers coping and self-esteem. Additionally, patient education and clinical stage impacted caregiver coping and self-esteem. Developing interventions to address caregiver coping, self-esteem, and resilience will prove beneficial in improving caregiver distress, anxiety, depression, burden, and perceived stress.

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.