New horizons in B-cell lymphoma immunotherapy: From immune checkpoints to precision medicine

Abstract

B-cell lymphoma, a malignancy in hematology with high heterogeneity, has its genesis and progression intricately associated with immune system regulation. Over the past three decades, transformative breakthroughs in B-cell malignancy investigations have emerged through paradigm-shifting molecular discoveries. Nevertheless, numerous hurdles persist in attaining a comprehensive understanding and effective treatment of this disease. Novel chemotherapeutic strategies demonstrate promising potential in B-cell lymphoma management, particularly through targeting immune checkpoints such as PD-1 (Programmed Cell Death Protein 1), LAG-3 (Lymphocyte-activation Gene 3), TIM-3 (T-cell Immunoglobulin and Mucin-domain containing-3), and TIGIT (T-cell Immunoreceptor with Ig and ITIM Domains) play pivotal regulatory roles within the immune system. These molecules critically orchestrate immune cell activation dynamics, proliferative capacity, and effector functions, thereby preserving immunological homeostasis. Deciphering the functional architecture of co-inhibitory checkpoints (e.g., PD-1/CTLA-4) in lymphomagenesis serves dual imperatives: deconstructing tumor immune evasion programs while establishing conceptual frameworks for precision immunotherapeutics development. PD-1 engagement with PD-L1/PD-L2 impairs T lymphocyte activation, facilitating tumor immune evasion. Deciphering these molecular processes enables therapeutic agents to employ targeted blockade strategies to restore antitumor immunity in lymphomas. Moreover, in-depth research on these checkpoints holds great promise for the discovery of novel biomarkers. These biomarkers may help predict responses to immunotherapy in lymphoma patients. This would enable clinicians to tailor personalized treatment plans for each patient, maximizing the therapeutic efficacy while minimizing unnecessary side-effects. Certain genetic signatures related to these immune checkpoints might be identified as predictors of a favorable response to PD-1 inhibitor-based immunotherapy. This analysis systematically deciphers the molecular interplay of PD-1/LAG-3/TIM-3/TIGIT immune checkpoint axes, delineating their regulatory dynamics in B-cell lymphomagenesis. It systematically summarizes the current research achievements, delves into the existing problems, and explores the future research directions. This approach seeks to advance dual contributions to fundamental science and clinical application in B-cell lymphoma immunotherapy, thereby facilitating therapeutic innovations while deepening mechanistic comprehension of disease pathogenesis. By doing so, it aims to provide valuable insights for both basic research and clinical translation in the field of B-cell lymphoma immunotherapy, ultimately enabling advancements in patient care and deeper insights into this multifaceted condition.