The tumour microenvironment in mycosis fungoides – decoupling biological and clinical responses

The tumour microenvironment (TME) plays a pivotal role in the progression of mycosis fungoides (MF), characterised by a shift in the immune response from a T helper (Th) 1 cell (Th1) to a Th2 cell profile. While this framework captures key features of disease progression, recent single-cell and spatial transcriptomic studies have further illuminated diverse malignant T-cell states, immune trajectories and spatial niches that extend beyond cytokine polarity alone. Skin-directed and systemic therapies for MF affect both malignant T-cells and the surrounding TME. The therapeutic response begins with biological changes in the TME, including tumour T-cell elimination via tumour cell killing and apoptosis, along with modification of the inflammatory milieu. Because these biological changes take time, early signs of clinical improvement may be subtle. Skin-related treatment-related adverse events, including inflammation, may occur and can be difficult to distinguish from ongoing disease. Given this overlap, careful clinical evaluation is warranted before changes to therapy are considered. It is therefore important to distinguish biological responses in the skin TME from clinical responses on the skin. In this article, we review data on biological and clinical responses to treatment in patients with MF and highlight the lack of biomarkers correlating with skin responses. Finally, we explore emerging tools and consider their potential to improve clinical decision-making when differentiating between biological and clinical responses.