Autoimmune diseases are a group of disorders characterized by an aberrant immune response, in which the immune system erroneously identifies tissue or organ self-proteins as foreign antigens, triggering immune responses that lead to tissue damage and functional impairment [1]. Their pathogenesis is influenced by a combination of genetic susceptibility (such as HLA alleles), environmental factors (including Epstein-Barr virus infection and gut microbiota dysbiosis), and disruption of immune homeostasis [2]. Aberrant activation of Th17 cells, dysfunction of regulatory T cells (Tregs), autoantibody production driven by B cells, and cytokine storms triggered by macrophages are all closely associated with the progression and exacerbation of AIDs [3,4]. Epidemiological data indicate that the global prevalence of AIDs continues to rise, which severely compromises quality of life and long-term prognosis. Common therapeutic approaches, including glucocorticoids, immunosuppressants, and certain biologics, can partially control disease activity. However, their efficacy remains limited, and long-term use is often associated with adverse effects such as osteoporosis, opportunistic infections, and drug resistance [5].

Although dendritic cells have long been considered the primary bridge between innate and adaptive immunity, increasing evidence suggests that macrophages also possess potent antigen-presenting capabilities within specific tissues and inflammatory microenvironments, playing a critical role in the pathogenesis of AIDs [6,7]. They exhibit high plasticity and functional diversity, are widely distributed across various tissues, and play essential immunoregulatory roles in multiple physiological processes, including immune tolerance, fibrosis, inflammatory responses, angiogenesis, and phagocytosis [8]. In autoimmune diseases, the phenotype and function of macrophages undergo significant alterations, which are closely associated with disease progression. Traditionally, they have been classified into classically activated pro-inflammatory M1 macrophages and alternatively activated anti-inflammatory M2 macrophages [9].

With the rapid development of high-resolution technologies such as scRNA-seq, researchers have been enabled to analyze the phenotypic diversity, developmental trajectories, and functional plasticity of myeloid cells, especially monocytes, macrophages, and dendritic cells, at the single-cell level in various tissues and pathological conditions [10]. This advancement has broken through the traditional classification system based on limited surface markers and challenged the conventional view that macrophages can be simply divided into M1 and M2 subtypes [11]. In addition, the concept of the macrophage niche has attracted increasing attention. This niche refers to the local stromal cells, metabolic factors, spatial signals, and signaling networks that collectively regulate macrophage residency, differentiation direction, and functional states through persistent imprinting effects [12].In this review, we primarily focus on the heterogeneity of macrophages in autoimmune diseases and summarize the newly identified macrophage subpopulations and their potential therapeutic targets in recent years. The aim is to provide new directions and strategies for clinical treatment and future research.