Beyond PD-1: Mechanisms of Resistance to Checkpoint Blockade in Classical Hodgkin Lymphoma and Next-Generation Immune Strategies.

PD-1 inhibitors have reshaped the treatment landscape of classical Hodgkin lymphoma, yet a substantial proportion of patients exhibit primary or acquired resistance driven by tumor-intrinsic alterations, immunosuppressive microenvironmental signals, metabolic constraints, and EBV-mediated modulation. This review summarizes key mechanisms underlying PD-1 resistance and highlights emerging biomarkers-including early F-FDG PET response, circulating tumor DNA kinetics, molecular subtyping, and spatial immune profiling-that enable early identification of nonresponders and support precision immunotherapy. Novel therapeutic strategies such as macrophage-targeted agents, metabolic modulators, bispecific antibodies, low-dose PD-1 regimens, and CD30-directed CAR-T cells show promise in overcoming resistance, particularly when integrated into adaptive, biomarker-guided treatment algorithms. Early incorporation of PET and ctDNA monitoring may inform timely treatment adaptation, while combination approaches addressing macrophage-driven suppression or redundant immune checkpoints should be considered in biologically high-risk patients. Overall, a deeper mechanistic understanding coupled with biomarker-driven stratification is essential to optimize PD-1-based therapy and improve long-term outcomes in cHL.