Targeting the Tumor Microenvironment in Hodgkin Lymphoma: Challenges and Therapeutic Strategies

Checkpoint inhibitors, particularly programmed cell death-1/programmed death-ligand 1 (PD-1/PD-L1) inhibitors, have significantly advanced the treatment of Hodgkin lymphoma (HL), especially in relapsed or refractory cases. However, challenges such as resistance, immune-related adverse events (irAEs), and the need for effective patient selection remain. This review aims to explore the mechanisms of resistance to checkpoint inhibitors, including alterations in the tumor microenvironment, loss of antigen presentation, and T-cell exhaustion. Overcoming resistance may involve combination therapies, such as pairing PD-1 inhibitors with other immune checkpoint inhibitors or targeted therapies like Brentuximab vedotin. Additionally, next-generation inhibitors targeting molecules like lymphocyte-activation gene 3 (LAG-3) and T-cell immunoglobulin and mucin-domain containing-3 (TIM-3) show promise in addressing resistance mechanisms not overcome by PD-1 inhibitors. Identifying reliable biomarkers to predict response to checkpoint inhibitors is critical for optimizing treatment, with ongoing research focusing on tumor mutational burden (TMB), inflammatory markers, and genetic profiling. Future clinical trials will aim to refine treatment regimens, optimize therapeutic combinations, and minimize adverse effects to maximize patient benefit.