• Mast cells, which release histamine, serotonin, and growth factors, show abnormal degranulation (the release of their internal granules) in diabetic wounds; excessive activation may sustain chronic inflammation.
• Dendritic cells, which link the innate and adaptive branches of immunity by presenting antigens, become less effective at efferocytosis (the removal of dead cells). When dead material accumulates, it keeps triggering inflammatory signals. Reduced activity of a transporter called SLC7A11 appears to weaken this process.
• Regulatory T cells, which normally suppress excessive immune activity, decline in both number and function, a reduction associated with slower healing.
• Dendritic epidermal T cells, a specialized skin population of γδ T cells, produce insulin-like growth factor 1 that helps keratinocytes multiply and close wounds; under diabetic conditions they show lower activation and reduced cytokine production.
• B cells and natural killer cells, less thoroughly studied, also contribute: B-cell recruitment appears to encourage macrophages to adopt M2 states, while natural killer cells help regulate inflammation and new blood vessel formation.

The scale of this coordination is the review's central point. Diabetes does not disable one cell type; it perturbs an entire network that must change composition over time as a wound moves through its inflammatory, proliferative, and remodeling stages.

What treatments could reprogram the immune response?

The authors argue that understanding this timing could open the door to therapies that directly modify immune activity rather than merely managing symptoms. Several approaches show promise:

• Topical anti-cytokine biologics (drugs that block persistent inflammatory signaling molecules).
• Drugs that encourage macrophages toward M2 states; several have shown an ability to speed wound closure, and macrophage-regulating drugs have shown benefits in randomized clinical trials.
• Mesenchymal stem cell therapies and extracellular vesicles (tiny membrane-bound particles released by cells) derived from them, which may offer broad immune-regulating effects.
• Advanced biomaterials and smart dressings that deliver immune-modifying substances directly to the wound.
• Janus liposozyme technologies designed to regulate redox balance, and IL-15 superagonists that boost the activity of dendritic epidermal T cells.

The findings remain preliminary in several respects. Much of the evidence comes from laboratory and early clinical work, and the authors themselves flag unresolved questions, including how macrophages should properly be classified. The M1/M2 framework, while widely used, simplifies a more complex biological reality.

Why timing may matter as much as targeting

The researchers emphasize that effective treatment may depend not only on which immune cells are targeted, but on when. Each healing phase carries a different immune environment, so a therapy useful at one stage may fail — or cause harm — at another.

Future approaches, they suggest, could include personalized treatment plans based on immune profiling of individual wounds, and combination therapies that target several immune cell populations at once. A wound treated during its inflammatory stage may require a wholly different intervention than the same wound weeks later.

For the millions of patients whose ulcers resist conventional care, the review offers a reframing: the wound is not simply failing to heal. The immune system is actively standing in its own way — and, with the right intervention at the right moment, that obstacle may prove correctable.