Spatiotemporal Heterogeneity of Macrophages in Acute Pancreatitis: From Inflammatory Initiators to Repair Coordinators and Targeted Therapeutics.

The current management of acute pancreatitis (AP) primarily relies on supportive measures, such as fluid resuscitation, nutritional support, and infection control. However, these approaches do not adequately address the core drivers of the disease. This limitation arises from an incomplete understanding of the progression from local injury to systemic inflammation and repair, which is a dynamic process with underlying immunoregulatory mechanisms that remain insufficiently characterized. Macrophages are the key effector cells involved throughout the disease course and exhibit pronounced spatiotemporal heterogeneity during this progression. Therefore, they are central to decoding the evolution of the disease and facilitating precise interventions. In terms of spatial dynamics, tissue-resident macrophages (TRMs), which are derived from embryonic sources, and monocyte-derived macrophages (MDMs) recruited from the bone marrow serve functionally complementary roles. Their relative dominance shifts in conjunction with disease progression rather than remaining static. Temporally, the macrophage phenotype undergoes a programmed evolution, beginning with an early phase dominated by M1 proinflammatory responses, transitioning through an intermediate phase where injury and repair coexist, and culminating in a late phase characterized by M2-dominated reparative coordination. This evolution is accompanied by corresponding metabolic reprogramming. Recent single-cell and spatial multiomics studies have unveiled a functional continuum that goes beyond the traditional M1/M2 dichotomy, revealing a rich diversity of cellular subsets and their spatial niches. This insight shifts targeting strategies from broad anti-inflammatory interventions toward more precise modulation aimed at specific phases, subsets, and regions. This review systematically examines the design principles, strengths, and limitations of three classes of intervention-molecular targeting, bioactive natural products, and nanoscale delivery-and identifies the obstacles that continue to impede their clinical translation. Building on this analysis, we propose a dual-dimensional (spatiotemporal) strategy of precise modulation, integrating single-cell and spatial omics, chronobiological principles, and the traditional Chinese medical concept of yin shi zhi yi (adapting treatment to timing), with the aim of shifting AP therapy from symptomatic support toward cause-directed repair.