Editorial: Synergistic Frontiers in Antibody-Based Immunotherapy for Hematological Malignancies

Weijie CaoLi YingmeiHaizhou XingZhongxing JiangJifeng Yu^*

• First Affiliated Hospital of Zhengzhou University, Zhengzhou, China

Antibody-based immunotherapy remains a cornerstone of modern treatment for B-cell and other hematologic malignancies, yet the discipline is evolving rapidly beyond single-agent anti-CD20 or PD-1 antibodies toward rational combination regimens, biomarker-guided precision, and strategies designed to overcome or preempt resistance. Unlike conventional chemotherapy, monoclonal antibodies and their derivatives enable targeted elimination of malignant clones while simultaneously recruiting the host immune system¹. However, their efficacy is often constrained by mechanisms of acquired resistance, immune escape, and the complex, dynamic architecture of the tumor microenvironment (TME)². This Research Topic seeks to deepen our understanding of antibody-driven therapies for hematologic cancers and to refine their clinical application. The four featured paperscomprising a case report of lenalidomide plus PD-1 blockade in relapsed/refractory classical Hodgkin lymphoma (cHL), a complex case of DLBCL with sequential antibody-based regimens and targeted maintenance, a bioinformatics analysis revealing hypoxia-induced mechanisms of rituximab resistance in DLBCL, and a focused review highlighting CD58 as a prognostic and immunotherapy-relevant antigen-collectively delineate the trajectory and future direction of antibody therapeutics. The following summary integrates their key insights and translational relevance. The DLBCL case involving multiple primary tumors illustrates the enduring centrality of antibody-based regimens in multidisciplinary care⁴. Rituximab-containing combinations produced sustained remission, while relapse was successfully managed through alternative antibody-based chemotherapies and subsequent maintenance with a BTK inhibitor. This treatment sequence-initial antibody therapy, salvage with antibody-containing regimens ± targeted agents, followed by maintenance-exemplifies the personalized therapeutic sequencing that defines modern hematologic oncology, while also highlighting both the durability and limitations of antibody-based interventions amid clonal evolution and comorbid malignancies. In their bioinformatics study, Yao et al.⁵ revealed that hypoxia within the tumor microenvironment induces a transcriptional signature associated with rituximab resistance in DLBCL. The authors identified a "DLBCL-hypoxia overlap" (DHO) gene set-includingLGALS1, TIMP1, ANXA1, STAP1, GPNMB, and CDCA7-that interacts with BCR and PI3K-AKT signaling pathways, both known to attenuate antibody-mediated cytotoxicity. These findings suggest that integrating anti-CD20 antibodies with inhibitors of hypoxia-adaptive signaling or metabolic modulators may restore therapeutic sensitivity and that DHO-related biomarkers could help identify patients at higher risk for treatment failure. Cao et al.⁶ provided an in-depth review of CD58 (LFA-3), an adhesion molecule critical for forming immunologic synapses through CD2 interactions. CD58 facilitates T-and NK-cell activation and is thus essential for the activity of bispecific antibodies and CAR-based therapies.Loss or mutation of CD58 correlates with poor prognosis and resistance to CAR-T and bispecific T-cell engager (BiTE) therapy-often mediated by increased PD-L1 expression and immune escape. Importantly, CD58 suppression can occur via EZH2-associated epigenetic silencing, suggesting that expression may be pharmacologically restored. Consequently, CD58 serves as both a biomarker for therapeutic selection and a potential target for intervention. Together, these studies outline a unified framework for advancing antibody-based immunotherapy in hematologic malignancies:1. Biomarker-guided personalization: Integration of hypoxia-related signatures with CD58 profiling can inform optimal therapeutic choices-anti-CD20 for hypoxialow/CD58-intact disease, combination or alternate pathways for hypoxia-high or CD58suppressed cases⁵ , ⁶.