IL-35: A Key Immunosuppressive Driver in Mycosis Fungoides Modulated by Phototherapy

Mycosis fungoides (MF) is the most common primary cutaneous T-cell lymphoma and is characterized by progressive immune dysregulation. Early disease often shows a T helper 1 (Th1) profile, while advanced stages shift toward an immunosuppressive T helper 2 (Th2) environment that promotes tumor persistence. Interleukin-35 (IL-35), a recently described member of the IL-12 cytokine family, has emerged as a potent immunosuppressive cytokine. It contributes to tumor growth by suppressing anti-tumor T-cell responses, expanding regulatory T cells, and fostering angiogenesis. Elevated IL-35 levels have been reported in several malignancies, including MF, but its behavior under therapeutic intervention has not been well defined. Phototherapy, including psoralen plus ultraviolet A (PUVA) and narrowband ultraviolet B (NB-UVB), remains a cornerstone treatment for early-stage MF. Beyond its direct cytotoxic effects on malignant T cells, phototherapy exerts broad immunomodulatory actions on the cutaneous cytokine milieu. Prior studies have shown normalization of cytokines such as IL-15 following phototherapy, suggesting that its benefits extend beyond lesion clearance to restoration of immune balance. This prospective interventional cohort study was designed to evaluate whether IL-35 levels in serum and skin tissue are altered by phototherapy in MF patients. Sixteen patients with histologically confirmed MF and sixteen matched healthy controls were enrolled. IL-35 was measured at baseline in both groups and again after phototherapy in patients. The study demonstrated that IL-35 levels were significantly elevated in MF patients compared to controls, and that both serum and tissue IL-35 declined after phototherapy, normalizing to control levels. These findings suggest that phototherapy may correct the immunosuppressive environment characteristic of MF, and that IL-35 could serve as a biomarker for disease activity and treatment response.