Targeting Tumor-associated Macrophages in Pancreatic Cancer

Tumor-associated macrophages (TAMs) constitute a major immune cell population within the pancreatic ductal adenocarcinoma (PDAC) tumor microenvironment (TME) 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 (CSF-1/CSF-1R), janus kinase/signal transducer and activator of transcription 3 (JAK/STAT3), phosphatidylinositol 3-kinase -γ (PI3K-γ), cluster of differentiation 40 (CD40), and toll-like receptor (TLR)-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, CSF-1R inhibitors, spleen tyrosine kinase (SYK) inhibitors, and TLR 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. • M2-polarized tumor-associated macrophages (TAMs) are pivotal drivers of immunosuppression and disease progression in pancreatic cancer (PC), with their abundance strongly correlating with poor patient prognosis. • Targeting TAMs via CSF-1R inhibition, STAT3 blockade, or CD40 agonism can reprogram the immunosuppressive tumor microenvironment (TME), reducing M2-like TAMs and promoting anti-tumor immunity. • Targeted TAM interventions, combined with programmed cell death protein 1/programmed cell death ligand 1 (PD-1/PD-L1) blockade or chemotherapy, have shown synergistic effects, improving T cell infiltration and function in preclinical and clinical studies. • Novel therapeutic avenues, such as inhibiting the galectin-9/T cell Immunoglobulin and Mucin-domain containing protein 3 (galectin-9/TIM-3) axis, SYK, or exosomal microRNA signaling, are emerging as promising strategies to disrupt pro-tumorigenic crosstalk between TAMs and cancer cells.