A scar like no other

A keloid is not simply a cosmetic defect. It is a pathological fibroproliferative disorder in which connective tissue overgrows beyond the boundaries of the original wound, does not regress spontaneously, and frequently recurs after treatment. Clinically, keloids present as dense, raised lesions that are often painful and pruritic, significantly impairing quality of life. Pathogenetically, they are characterized by persistent inflammation, excessive deposition of type I and III collagen, disrupted extracellular matrix (ECM) remodeling, and pathological angiogenesis [1]. Predicting who will develop a keloid after injury remains extremely difficult: genetic predisposition, the nature and location of the injury, the inflammatory response, and ECM metabolism all play a role [2]. Current treatment standards are predominantly local and multimodal — intralesional corticosteroids, compression therapy, laser therapy, surgery — yet none consistently achieve stable outcomes in all patients.

For a long time, keloid research focused primarily on fibroblasts as the direct "builders" of the pathological scar. However, evidence accumulated in recent years strongly suggests that immune dysregulation creates the environment in which fibrosis becomes both possible and uncontrollable. Multiple studies have documented markedly elevated cytokine levels in keloid patients — so pronounced that some authors consider this a sign of a systemic autoinflammatory component [3]. A natural question arose: which specific cellular mechanisms drive this dysregulation, and can they be exploited as therapeutic targets?

Aim and design of the review

To address this question, a team of Chinese researchers published a review article in Annals of Medicine in 2026, integrating data from clinical and translational studies — including findings from single-cell RNA sequencing (scRNA-seq) — into a unified framework [1]. The aim was to construct a systematic picture of the keloid immune microenvironment, characterize the role of each key cell population, and identify specific intervention points for future therapy.

"Low inflammation — high fibrosis": a cellular portrait of keloid

The authors describe the keloid immune microenvironment as a state of "low inflammation — high fibrosis." Outwardly, it does not resemble classic acute inflammation, yet this precise combination provides the conditions for sustained fibrotic tissue expansion. At the center of the pathological process lies a mutually reinforcing loop between regulatory T cells (Tregs) and M2-polarized macrophages.

Tregs secrete IL-10 and transforming growth factor beta (TGF-β). By suppressing normal inflammatory responses, they simultaneously stimulate fibroblast hyperproliferation and excessive collagen deposition. M2-like macrophages — the predominant macrophage phenotype in keloid tissue — release TGF-β1 and platelet-derived growth factor BB (PDGF-BB), shifting the balance of ECM synthesis and degradation toward accumulation. Tregs and M2 macrophages sustain each other, forming a closed pro-fibrotic loop that the tissue cannot exit on its own.

At the opposite pole of this system lies the suppression of cytotoxic cells. CD8+ T cells and natural killer (NK) cells in keloid tissue are functionally exhausted. The NKG2A/CD94 axis — an inhibitory receptor complex — plays a key role, depriving these cells of their ability to eliminate aberrant fibroblasts. In parallel, tolerogenic dendritic cells dampen anti-fibrotic inflammatory signals. In contrast, myeloid-derived suppressor cells (MDSCs) create an immunosuppressive niche through the secretion of TGF-β and arginase-1 and directly activate fibroblasts.

A dedicated section of the review addresses tissue-resident memory T cells (TRM) — long-lived T cells that persist in scar tissue after treatment. The authors propose that TRM may provide a local immunological "memory" that explains why surgical excision of a keloid often merely triggers a new cycle of fibrosis.

Therapeutic targets

The mechanisms described point to several concrete directions for targeted intervention.

The first is blockade of the IL-4Rα pathway using dupilumab, already well established in atopic dermatitis. To evaluate its efficacy in keloids, a randomized placebo-controlled trial (NCT04988022) and an open-label study (NCT05128383) have been initiated.

The second is restoration of cytotoxic function in NK cells and CD8+ T cells through inhibition of the NKG2A/CD94 axis. The monoclonal antibody monalizumab is discussed as a potential candidate.

The third is modulation of macrophage polarization: the pro-fibrotic M2 phenotype predominates in keloid tissue, and shifting it toward a less pro-fibrotic state is considered an independent therapeutic target. In a randomized study with pre- and post-treatment biopsies, patients who responded to intralesional therapy showed redistribution of macrophage programs alongside changes in Treg-associated signals. Specific clinical drug candidates for this approach are not named in the review; however, TGF-β blockade and inhibition of colony-stimulating factor 1 receptor (CSF1R) rapidly reduced collagen production in experimental models, supporting the validity of these targets.

Separately, the authors mention botulinum toxin type A as an adjuvant in combination with surgical excision: in a study of auricular keloids, immediate postoperative injection improved cosmetic outcomes — presumably through a reduction in mechanical tissue tension and indirect effects on the local cytokine environment.

Safety and limitations

The authors are candid about the limitations of the available evidence. Clinical data for most targeted approaches remain limited, and randomized controlled trials designed around specific immune mechanisms are still scarce. For monalizumab, the authors note that although the agent can enhance immune responses, its adverse-effect profile in keloids warrants further investigation. For cell-based therapeutic strategies, long-term stability and safety remain priorities. The role of NK cells in pathogenesis is less fully characterized than that of macrophages or Tregs. Whether TRM directly drives recurrence requires prospective studies that correlate treatment outcomes.

Practical significance and conclusion

This review offers a fundamentally different perspective on the nature of keloids — not as a defect caused exclusively by aberrant fibroblasts, but as an immune-mediated condition with well-defined cellular targets. For the practicing specialist, this means that in the future, treatment selection may be guided not only by scar location and size, but also by the individual patient's immune profile. Biomarkers — such as the Treg-to-cytotoxic cell ratio or the degree of M2 macrophage polarization in a biopsy — may eventually become tools for personalizing treatment and predicting recurrence.

The keloid immune microenvironment is not a background process but an active participant in pathogenesis. The imbalance between immunosuppressive cells (Tregs, M2 macrophages, tolerogenic dendritic cells, MDSCs) and functionally exhausted cytotoxic cells (CD8+ T cells, NK cells) creates conditions in which fibroblasts produce collagen unchecked, and the pathological scar persists — and returns. The systematic mapping of these mechanisms, undertaken by the authors of this review, provides, for the first time, a comprehensive picture of immune "complicity" in keloid development. Clinical trials of targeted approaches are already underway. The task for specialists is to follow their results and be prepared for a fundamental reassessment of treatment principles for one of the most therapeutically challenging conditions in dermatology and aesthetic medicine.

References

1. Wu Y., Huang Y., Zhang H. et al. Immune cells in keloids: mechanisms and potential treatments. Ann Med 2026; 58(1): 2655499.
2. Latoni D.I., McDaniel D.C., Tsao H. et al. Update on the pathogenesis of keloid formation. JID Innov 2024; 4(6): 100299.
3. Nangole F.W., Ouyang K., Anzala O. et al. Multiple cytokines are elevated in patients with keloids: is it an indication of auto-inflammatory disease? J Inflamm Res 2021; 14: 2465–2470.
4. Olopoenia A., Yamaguchi Y., Peeva E. et al. Demographics, clinical characteristics, and treatment patterns among keloid patients: United States Electronic Health Records (EHR) Database Study. Int J Dermatol 2024; 63(8): e163–e170.