Tissue-Resident Macrophage in Inflammation and Cancer

Tissue-resident macrophages (TRMs) are long-lived immune cells strategically distributed across organs, where their functional plasticity enables both homeostatic maintenance and pathological dysfunction. This review provides a comprehensive analysis of TRM biology in inflammation and cancer. We first delineate the heterogeneity and developmental origins of TRM subsets across organs, highlighting how organ-specific niche signals create distinct vulnerability patterns. We then dissect macrophage dysfunction during sepsis, tracing their trajectory from protective anti-infectious immunity through critical tipping points to immunoparalysis. Next, we examine additional inflammatory contexts, including sterile inflammation, autoimmune inflammation, Type 2 inflammation, and metabolic inflammation, each revealing distinct facets of macrophage functional plasticity. In parallel, we examine how the tumor microenvironment chronically co-opts TRMs, transforming them into tumor-associated macrophages that promote angiogenesis, suppress antitumor immunity, facilitate metastasis, and support cancer stem cells (CSCs). Then, a systematic cross-disease comparison reveals shared mechanisms that underlie the opposing functional outputs of macrophages in inflammation and cancer. Finally, we evaluate emerging therapeutic strategies and propose a paradigm shift from functional blockade toward precise recalibration of macrophage function to restore immune balance across both disease categories. Together, this review highlights the therapeutic potential of targeting shared macrophage regulatory nodes to restore immune balance across inflammation and cancer.