CD169-positive macrophages in lymph nodes and the tumor microenvironment: harnessing their biology for clinical diagnosis and anticancer therapeutic strategies.

CD169+ macrophages are strategically positioned in secondary lymphoid organs and diverse peripheral tissues, where they orchestrate tissue-specific immune homeostasis by regulating local cellular and humoral responses. In the context of cancer, CD169+ macrophages within tumor-draining lymph nodes (tdLNs) and the tumor microenvironment (TME) have emerged as critical determinants of clinical outcome across multiple malignancies, acting as key modulators of both tumor progression and tumor control. In this review, we delineate the distinct yet complementary roles of CD169+ macrophages in tdLNs and the TME, with particular emphasis on their molecular and cellular interactions with cancer cells and immune effector populations, and on how these interactions shape systemic anticancer immunity. We further discuss the translational significance of CD169+ macrophages as prognostic and predictive biomarkers, and propose immunotherapeutic strategies that selectively target or exploit these cells to enhance antitumor responses. By integrating current experimental and clinical evidence, this review aims to refine our understanding of CD169+ macrophage biology and to highlight their potential as actionable targets in cancer diagnosis and treatment.