BACKGROUND: Despite novel therapeutic options, the long-term management of cutaneous T cell lymphoma (CTCL) remains challenging. Extracorporeal photopheresis (ECP) is an immunomodulating photochemotherapy associated with higher overall survival when used for the treatment of leukemic forms of CTCL. Its exact mode of action is not fully elucidated. Immunogenic cell death (ICD) is pivotal in cancer immunotherapy, marked by the release of damage-associated molecular patterns that enhance dendritic cell (DC) maturation and cytotoxic T lymphocyte responses. OBJECTIVES: This study explores ICD in patients with leukemic forms of CTCL during ECP and its effect on DC activation. METHODS: We conducted in vitro studies with peripheral blood mononuclear cells (PBMCs) from healthy donors and ex vivo experiments with white blood cells (WBCs) from patients with leukemic forms of CTCL undergoing ECP. We assessed cell viability, apoptosis, and ICD markers (ATP, HMGB1, calreticulin) using flow cytometry, ELISA, and qPCR. Engulfment assays evaluated DC activation by ECP-treated CD4+ T cells. RESULTS: ECP-treated healthy PBMCs and WBCs from patients with leukemic forms of CTCL showed significant induction of ICD hallmarks, including ATP release, HMGB1 secretion, and calreticulin surface exposure. In the patients with leukemic forms of CTCL, calreticulin expression was mainly present in CD4+CD26- T cells, indicating greater ICD susceptibility of malignant T cells. ECP-treated CD4+ T cells were phagocytosed by DCs, a process which we found to be dependent on ICD signals. CONCLUSIONS: ECP induces ICD in malignant T cells and, to a lesser extent, in healthy T cells, facilitating DC activation. These findings suggest that ECP enhances targeted immune responses against malignant T cells in leukemic forms of CTCL, offering new insights into its therapeutic mechanisms and potential applications in cancer immunotherapy.