Targeting Metabolism to Control Effector and Regulatory T Cells

Rachael Clark, MD, PhD, of Brigham Children's Hospital in Boston, MA, presented compelling new evidence at the 2025 Inflammatory Skin Disease Summit on the role of mitochondrial metabolism in controlling skin inflammation. Her work highlights the centrality of mitochondria not only as energy producers but also as regulators of immune responses, with implications for both inflammatory skin diseases and cutaneous malignancies.¹

Mitochondria as Master Regulators of Inflammation

Clark emphasized that “mitochondria are master regulators of inflammation, completely independent of their ability to generate energy.” This assertion is grounded in 3 lines of investigation from her laboratory: studies of tepinoroth, immune evasion mechanisms in mycosis fungoides (MF), and radiation responses in human skin. Across these models, mitochondria were shown to act as “exquisitely sensitive intercellular danger sensors that profoundly affect the inflammatory tone inside cells,” influencing both stromal and immune cell behavior.

Central to these findings is the concept of cytoplasmic nucleic acid sensing. Mitochondria, retaining bacterial-like DNA and RNA from their evolutionary origin, can release these nucleic acids into the cytoplasm, triggering innate immune pathways.² Clark noted, “Did you know that when you respond to influenza, you are not responding to the virus? The virus itself causes the release of mitochondrial DNA that kicks off a type one interferon response.” This mitochondrial danger-associated molecular pattern (DAMP) signaling orchestrates immune cell activation, cytokine production, and inflammation.

Tepinoroth and Metabolic Modulation in Psoriasis

Tepinoroth, a novel HR topical agonist, has demonstrated durable immunomodulatory effects in psoriasis, affecting multiple immune cell types and cytokine pathways. Clark’s team found that tepinoroth treatment in human skin graft models reduced epidermal thickness, T cell infiltration, and expression of over 3,000 genes. Pathway analyses revealed broad downregulation of type 1, type 2, and type 17 inflammatory cytokines, as well as suppression of cytoplasmic nucleic acid sensing.

Mechanistically, Clark stated tepinoroth appears to act at the mitochondrial level. It reduces mitochondrial reactive oxygen species (ROS) and limits the release of mitochondrial DNA, leading to decreased DAMP signaling. Clark explained, “Mitochondria can actually set inflammatory tone by the amount of self DAMPs they release, and certain amount are released at baseline, and that is controlled at least in part by mitochondrial ROS levels.” Additionally, tepinoroth impairs glycolysis, fatty acid oxidation, and glutamate metabolism in T cells and keratinocytes, inducing a state of metabolic quiescence that may contribute to long-term remission.

Insights from Cutaneous T Cell Lymphoma

The translational relevance of mitochondrial modulation extends to cutaneous T cell lymphoma (CTCL). In untreated MF lesions, benign immune cells exhibited reduced cytoplasmic nucleic acid sensing and downstream pathway activation. Following topical treatment with the TLR7/8 agonist resiquimod, Clark’s team observed enhanced DAMP signaling, restoration of metabolic activity, and elimination of malignant T cells. Remarkably, “despite its inflamed appearance, if you biopsy a lesion of MF and you look only at the benign cells…they’re actually less activated than the immune cells in healthy skin.” This demonstrates the capacity of targeted mitochondrial interventions to reverse immune evasion in cancer.

Radiation as a Modulator of Mitochondrial-Driven Inflammation

Further illustrating the universality of mitochondrial regulation, low-dose radiation induced a robust inflammatory response in human skin grafts. One gray of radiation triggered polyclonal proliferation of T cells and upregulation of type I interferon pathways across multiple cell types. Clark noted, “Low dose radiation causes widespread activation of immune and stromal cell types, probably by inducing mitochondrial DAMPs.” This suggests potential clinical applications for radiation as an adjuvant to enhance anti-tumor immunity, particularly in “cold” tumors resistant to checkpoint blockade.

Implications and Future Research

Clark’s work emphasizes that therapeutic modulation of mitochondrial metabolism can finely tune immune responses in the skin. Both immunosuppressive (tepinoroth, chimerin) and pro-inflammatory (resiquimod, low-dose radiation) interventions converge on mitochondria to control immune cell behavior. The findings highlight the possibility of targeting resident memory T cells in chronic inflammatory diseases and manipulating metabolic pathways to enhance anti-cancer immunity.

In conclusion, Clark underscored, “Mitochondria are more than just energy producers. They’re danger sensors. They reflect immune cell biology. But if you intervene at the level with drugs or other interventions, you can actually control immune cell data.” These insights provide a roadmap for innovative therapies that leverage mitochondrial biology to modulate skin inflammation and immunity, offering clinicians a mechanistic framework for future interventions.

References

1. Clark R. Harnessing metabolism to control skin inflammation. Oral presentation. Presented at: Inflammatory Skin Disease Summit 2025; November 12-15, 2025; New York, New York.
2. Ludwig-Słomczyńska AH, Seweryn MT, Wiater J, et al. Cytosolic nucleic acid sensing and mitochondrial transcriptomic changes as early triggers of metabolic disease in db/db mice. Mamm Genome. 2024;35(1):68-76. doi:10.1007/s00335-023-10026-z