Monocyte-Macrophage Lineages in Cancer: Biology, Plasticity, and Therapeutic Targeting

Monocytes are highly plastic innate immune cells that serve as critical sentinels of host defense, tissue homeostasis, and inflammatory regulation. Beyond their canonical functions in phagocytosis, cytokine and chemokine production, and antigen presentation, monocytes play increasingly recognized roles in shaping the tumor ecosystem. In cancer, malignant cells and their associated stromal networks profoundly reprogram monocyte development, trafficking, and functional states, converting these cells from immune defenders into key facilitators of tumor initiation, progression, and therapeutic resistance. Upon infiltration into the tumor microenvironment (TME), circulating monocytes differentiate into heterogeneous populations of tumor-associated macrophages (TAMs) that support cancer cell survival, angiogenesis, immune suppression, and metastatic dissemination. Recent advances in single-cell transcriptomics, spatial profiling, lineage tracing, and high-dimensional cytometry have transformed our understanding of monocyte and macrophage biology, revealing previously unappreciated diversity in their ontogeny, phenotypic states, and context-dependent functions across tumor types and disease stages. These technologies have uncovered dynamic crosstalk between monocytes, TAMs, cancer cells, and other immune and stromal components, highlighting monocyte-derived populations as central regulators of the immunosuppressive TME. In this Review, we synthesize current insights into the functional heterogeneity of monocyte and macrophage subsets in cancer, emphasizing their roles in tumorigenesis, immune evasion, and therapeutic responses. We further discuss emerging therapeutic strategies aimed at targeting monocyte recruitment, differentiation, and effector functions, including macrophage reprogramming, depletion, and combinatorial approaches with immunotherapy. Collectively, these advances position monocytes and their progeny as both biomarkers and actionable targets, offering new opportunities to reshape the tumor immune landscape for durable cancer control.