Feeding the fire: How inflammation may sustain mycosis fungoides and Sézary syndrome – and options to disrupt

Cutaneous T-cell lymphomas (CTCL), including mycosis fungoides (MF) and Sézary syndrome (SS), are histopathologically characterized by a prominent inflammatory infiltrate, accompanying the malignant cells in the skin. This infiltrate contributes to diagnostic uncertainty and appears to support the persistence of malignant T cells. Growing evidence supports an inflammation-driven disease model, in which cytokine networks, microbial triggers, and direct cellular interactions shape a tumor-permissive microenvironment. In this perspective, we discuss how established skin-directed therapies achieve clinical benefits not only by directly affecting malignant cells, but also by remodeling the lesional immune milieu and reducing supportive inflammatory infiltrates. We also highlight the importance of targeting microenvironmental signaling pathways, focusing on the OX40/OX40L costimulatory axis and JAK/STAT pathway dysregulation as therapeutic targets. Overall, we propose that integrating tumor-directed therapy with approaches that modify the inflammatory niche may offer a rational strategy to improve long-term disease control in MF/SS.