Spatial Transcriptomic Profiling of Tumor-Associated Macrophage Polarization States Mediated by TGF-β1 Signaling Gradient in Pancreatic Ductal Adenocarcinoma Microenvironment

This literature review will examine the spatial heterogeneity and functional plasticity of tumor-associated macrophages (TAMs) within the pancreatic ductal adenocarcinoma (PDAC) microenvironment, emphasizing how gradients of transforming growth factor-beta 1 (TGF-β1) regulate macrophage polarization and contribute to tumor progression. Particular attention will be given to the dynamic spectrum of macrophage activation states, moving beyond the conventional M1/M2 framework to explore the continuum of transcriptional and functional phenotypes observed in vivo. The review will synthesize current understanding of how interactions among malignant cells, cancer-associated fibroblasts, immune cells, and extracellular matrix components establish localized TGF-β1 signaling environments that shape macrophage behavior and promote immune suppression, fibrosis, angiogenesis, and metastatic dissemination.

The review will further explore advances in spatial transcriptomic technologies, including platforms such as 10x Genomics Visium, MERFISH, and Slide-seq, that have transformed the study of cellular organization within intact tissues by preserving spatial context alongside gene expression profiles. Recent literature employing these technologies will be evaluated to characterize the spatial distribution of macrophage populations throughout PDAC and identify transcriptional programs associated with distinct microenvironmental niches. Particular focus will be placed on the molecular mechanisms through which TGF-β1 activates canonical SMAD-dependent signaling and non-canonical pathways involving NF-κB, MAPK, PI3K-AKT, and STAT signaling to regulate macrophage differentiation, plasticity, and functional specialization. Finally, this review will assess the implications of spatially organized macrophage populations for disease progression, therapeutic resistance, and emerging treatment strategies. Studies examining the influence of TGF-β1-mediated macrophage polarization on extracellular matrix remodeling, cytotoxic T-cell exclusion, chemotherapy resistance, and immune checkpoint inhibitor efficacy will be critically analyzed alongside recent efforts to therapeutically target these pathways through TGF-β receptor inhibition, CSF-1R blockade, macrophage reprogramming, and combination immunotherapies. By integrating findings from spatial transcriptomics, immunology, and computational biology, this review aims to evaluate current evidence supporting TGF-β1 as a central regulator of macrophage spatial organization in PDAC while identifying unresolved questions and future directions for precision immuno-oncology research.