Immune Dysregulation, Compartment-Specific Biology, and Therapeutic Biomarkers in Mycosis Fungoides and Sézary Syndrome.

Cutaneous T-cell lymphoma (CTCL), including mycosis fungoides (MF) and Sézary syndrome (SS), is defined by malignant CD4+ T-cell clones that evolve within and remodel the skin and systemic immune compartments. For disease biology and immune remodeling, we prioritize evidence from human primary samples; for therapeutic implications, we integrate clinical-trial and translational biomarker studies. We organize evidence by compartment (skin vs. blood) and, within skin, by stage (patch/plaque vs. tumor). Early patch/plaque MF often shows features consistent with constrained inflammation: skin-resident memory T-cell (TRM)-like malignant clones are in a Th1-leaning microenvironment with relatively preserved cytotoxic surveillance. Progression to tumor-stage MF (and/or large-cell transformation) is frequently associated with clonal dominance, Th2 cytokine polarization, upregulation of checkpoint pathways, and remodeling of myeloid/fibroblast populations. SS is typically associated with leukemic clonal dominance, systemic Th2 skewing, and broad impairment of cytotoxic immune control. These trajectories support an interpretive framework that aligns immune-directed therapies with compartment- and stage-associated biology; these include strategies that (i) deplete malignant clones (e.g., CCR4, CD30, KIR3DL2 targeting), (ii) re-engage exhausted effectors (PD-1/PD-L1 axis), (iii) reprogram cytokine balance (IFN-γ, IL-12, extracorporeal photopheresis), or (iv) suppress malignant signaling programs with secondary immune effects (JAK/STAT inhibition). We highlight potential candidate predictive biomarkers at varying levels of maturity, most of which require prospective validation, including antigen density, compartmental tumor burden, tumor cell fraction, effector-cell substrate, and interferon/cytokine signatures.