Reshaping the TME to enhance checkpoint blockade in ENKTL

In this issue of Blood, Kim et al 1 present compelling findings from a phase 2 trial exploring the combination of cemiplimab, an anti-programmed death-1 (anti-PD-1) antibody, and isatuximab, an anti-CD38 antibody, in relapsed or refractory (R/R) extranodal natural killer/T-cell lymphoma (ENKTL).Although L-asparaginase-based chemotherapy remains effective in frontline settings, 2 outcomes for patients with R/R disease are dismal, emphasizing the urgent need for innovative therapeutic strategies.Given this background, the results presented by Kim et al are encouraging.The authors demonstrate that CD38 cotargeting can enhance the efficacy of PD-1 blockade, achieving a complete response (CR) rate of 51% and an overall response rate of 65% in 37 treated patients.Importantly, the responses were durable, with a median duration of 21 months.Notably, responders exhibited high programmed death ligand 1 (PD-L1) expression and structural variations in the PD-L1 3'untranslated region, suggesting a potential biomarker for response.The combination therapy was well tolerated, with no treatment-related deaths.These promising results raise a key question: Can CD38 inhibition unlock the full therapeutic potential of PD-1 blockade in ENKTL?