Tumor-associated macrophages (TAMs) constitute a major immune cell population within the pancreatic ductal adenocarcinoma (PDAC) tumor microenvironment and play pivotal roles in tumor progression, immune evasion, stromal remodeling, and therapeutic resistance. Classically activated M1 macrophages generally exert anti-tumor effects, while alternatively activated M2-like macrophages predominantly facilitate tumor growth and immunosuppression. In this review, we aim to systematically summarize the current understanding of TAM polarization, subtype-specific functions, and emerging macrophage-targeted therapeutic strategies in PDAC, with particular emphasis on translational advances and existing clinical challenges. A comprehensive literature review was conducted focusing on TAM biology, key signaling pathways involved in macrophage polarization, preclinical therapeutic approaches, and currently available clinical trial evidence in PDAC. Multiple signaling pathways, including colony-stimulating factor 1/colony stimulating factor 1 receptor, janus kinase/signal transducer and activator of transcription 3 (JAK/STAT3), phosphatidylinositol 3-kinase -γ, cluster of differentiation 40, and toll-like receptor-associated pathways, have been implicated in TAM polarization in PDAC. Current therapeutic strategies mainly involve promoting M1 polarization, depleting M2-like macrophages, and reprogramming immunosuppressive TAMs toward anti-tumor phenotypes. Promising therapeutic agents include selicrelumab, ruxolitinib, colony stimulating factor 1 receptor inhibitors, spleen tyrosine kinase inhibitors, and Toll-like receptor agonists. In addition, neoadjuvant FOLFIRINOX chemotherapy may enhance M1-like macrophage infiltration through immunogenic cell death and TME remodeling. However, several strategies remain largely at the preclinical stage. Direct evidence supporting certain subtype-specific mechanisms, particularly those involving M2b macrophages in PDAC, remains limited. Overall, TAM-targeted therapy represents a promising immunotherapeutic strategy for PDAC. Future clinical translation will depend on improved target specificity, biomarker-guided patient stratification, and rational combination therapeutic approaches.

Pancreatic cancer (PC) is a highly malignant neoplasm of the digestive system. The primary objective of this investigation is to elucidate the intricate mechanisms underlying the role of the aging process and the related factor Epithelial membrane protein 1 (EMP1) in PC progression. We established a prognostic model pertinent to the aging process that could be applied in postoperative PC patients. In vitro assays were employed to elucidate the impact of EMP1 on PC cell function. We employed lentiviral vectors for both knockdown and overexpression of EMP1 in Panc02 cells, followed by the establishment of subcutaneous, pulmonary metastasis, and orthotopic pancreatic liver metastasis models in mice. Using tissue microarrays, we evaluated the expression of EMP1 and its downstream entities, and then conducted clinical correlation analysis. A predictive Age-Related Score (ARS) system based on age-associated prognostic genes was developed, offering precise prognostic predictions for postoperative PC patients, which could be applied well at the single-cell level, showing diverse aging, epithelial–mesenchymal transition (EMT), cell migration, cell proliferation, and PI3K/AKT signaling activity in high and low ARS risk cells. EMP1 was identified as a pivotal molecule in the ARS system and is associated with poor prognosis. Besides, EMP1 could enhance the proliferation, migration, and invasion of PC cells both in vitro and in vivo by augmenting the PI3K/AKT signaling cascade. In essence, this research formulated an aging-centric prognostic model for postoperative PC and pinpointed EMP1 as an oncogenic factor facilitating tumor cell EMT during the aging trajectory in resectable PC patients.