Enhancing PD-1 blockade efficacy through CD38 inhibition. The figure illustrates potential mechanisms through which combining the PD-1 inhibitor cemiplimab (orange) with the CD38 monoclonal antibody isatuximab (black) may amplify immune checkpoint blockade in ENKTL. (I) Direct CD38-mediated cell killing: isatuximab induces direct cytotoxicity against ENKTL cells (violet), which have CD38 expression that is further upregulated in response to PD-1 blockade.⁴ (II) Reducing Treg-mediated immunosuppression: isatuximab eliminates immunosuppressive CD38-positive Tregs (red), promoting a more immune-permissive tumor microenvironment and boosting antitumor immunity.⁴ (III) Restoring cytotoxic CD8⁺ T-cell function: PD-1 inhibition with cemiplimab activates cytotoxic T cells (green). However, compensatory upregulation of CD38 in malignant cells, driven by factors like ATRA and IFNβ (black arrows), suppresses cytotoxic T-cell function.⁸ CD38 plays an important role as an ectoenzyme in metabolizing NAD and generating adenosine, which activates ADORs on cytotoxic T cells, dampening their function (black dotted arrow).⁴ By blocking CD38, isatuximab disrupts this resistance mechanism (black inhibitor), potentially enhancing and prolonging the efficacy of PD-1 blockade. ADOR, adenosine receptor; ATRA, all-trans retinoic acid; IFNβ, interferon-β; NAD, nicotinamide adenine dinucleotide. Figure created in BioRender (https://BioRender.com/y93h678).