Tissue-Resident Macrophages: Origins and Functions in Homeostasis and the Tumor Microenvironment

TRMs (tissue-resident macrophages) are cornerstone cells of the innate immune system, fundamentally shaping local immunity and tissue adaptation. Primarily derived from the embryonic yolksac, these self-maintaining populations are integral to adult tissue homeostasis. As critical components of the TME (tumor microenvironment), TRMs exhibit profound phenotypic plasticity and functional heterogeneity, orchestrating complex effects that range from tumor immune surveillance to promoting malignant progression. The challenge of modulating TRMs stems from their high adaptability and complex ontogeny-function linkages. While early therapeutic strategies relied on non-specific depletion or blockade of monocyte recruitment, the field has rapidly advanced toward precision functional reprogramming. Current leading approaches focus on multimodal interventions, including targeted metabolic and epigenetic modulation, sophisticated cellular engineering, and the use of small molecules to attenuate or reverse pro-tumorigenic phenotypes. Achieving effective clinical translation requires overcoming major bottlenecks: establishing a deeper, single-cell resolution understanding of the mechanisms governing TRM plasticity and subset identity, and developing robust, subset-specific targeting modalities. The rational design of sophisticated combination therapies remains the critical frontier for maximizing the clinical efficacy of macrophage-based cancer immunotherapy.

CSTR: 32200.14.cjcb.2026.05.0002