Tumor- and host-related factors regulate sensitivity to ECP and have therapeutic implications. Tumor-associated factors, including tumor immunogenicity and characteristics of the tumor microenvironment (TME), and host-related factors related to disease progression and treatment history, regulate the balance between effective tumor immunity and immune evasion/suppression. Therefore, the identification of surrogate biomarkers for these relevant tumor and host characteristics may facilitate a more personalized selection of rationale therapeutic strategies. A minority of eMF/SS patients, as suggested by the ≈10% complete response rate associated with ECP monotherapy, harbors an immunogenic tumor and is able to generate an effective antitumor immune response following ECP that is not overwhelmed by immunosuppressive mechanisms with the TME. In contrast to these patients for whom ECP monotherapy may be sufficient, most patients may benefit from combination strategies with novel agents that either deplete immunosuppressive constituents of the TME (eg, regulatory T cell depletion with mogamulizumab [Moga]) or block dominant immune checkpoints (eg, checkpoint blockade [CPB]). In contrast, epigenetic therapies (including histone deacetylase inhibitors [HDACi]), by inducing the expression of neoantigens, may be useful in a subset of patients with poorly immunogenic tumors. Conversely, immunologically incompetent patients with poorly immunogenic tumors may not benefit from immunotherapeutic strategies, including ECP. Novel therapeutic strategies are needed for these patients, and clinical trial participation should be encouraged. Mϕ, macrophage; PD-L1, programmed death-ligand 1.