Editorial: New molecular targets for personalized treatment for low-grade non-hodgkin lymphoma

The therapeutic landscape of low-grade non-Hodgkin lymphoma (LG-NHL) has evolved considerably over the past decade, driven by advances in molecular biology, genomic profiling, and cancer immunology (1–3). These developments have accelerated the transition from conventional chemoimmunotherapy to precision medicine, in which treatment decisions are increasingly guided by the molecular and genomic characteristics of individual patients (4–10). Targeted therapies, immune-based approaches, and biomarker-driven risk stratification are reshaping clinical practice, offering opportunities to improve efficacy while minimizing treatment-related toxicity (5, 11–14). Despite these advances, disease heterogeneity, therapeutic resistance, and relapse remain significant challenges, underscoring the need to identify new molecular targets and develop more effective personalized therapeutic strategies (15–18).

This Research Topic, New Molecular Targets for Personalized Treatment for Low-Grade Non-Hodgkin Lymphoma, highlights recent advances spanning laboratory investigations, clinical studies, translational research, comprehensive reviews, and an instructive case report. Although the articles focus on distinct lymphoma subtypes and their therapeutic approaches, including 3 about low-grade lymphomas and 3 of aggressive lymphomas, they share the common objective: improving patient outcomes through a deeper understanding of lymphoma biology and the development of individualized therapeutic interventions.

The original research article “Dual targeting of EZH2 and PD-L1 in Burkitt’s lymphoma enhances immune activation and induces apoptotic pathway” investigates the interaction between epigenetic regulation and tumor immunity. The authors demonstrate that simultaneous inhibition of the histone methyltransferase EZH2 and the immune checkpoint molecule PD-L1 produces synergistic antitumor activity, increasing apoptosis while promoting immune activation. These findings support the concept that epigenetic remodeling can enhance immune-mediated tumor elimination and provide a strong rationale for combining targeted epigenetic therapy with immunotherapy. Although Burkitt lymphoma is an aggressive lymphoma rather than a low-grade subtype, the biological mechanisms explored are broadly applicable across low-grade B-cell lymphomas and illustrate the expanding potential of rational combination therapies.

Complementing these mechanistic findings, the review article “The therapeutic perspective of relapsed/refractory Waldenström Macroglobulinemia: what comes next?” summarizes the rapidly evolving therapeutic options for patients with relapsed or refractory disease. Waldenström macroglobulinemia has become a model for precision medicine because treatment selection increasingly depends on molecular alterations, including MYD88 and CXCR4 mutations. The review discusses advances in next-generation Bruton tyrosine kinase inhibitors, BCL2 inhibition, CXCR4-targeted agents, bispecific antibodies, antibody-drug conjugates, and chimeric antigen receptor T-cell therapy. Beyond describing emerging drugs, the authors emphasize individualized treatment selection, therapeutic sequencing, and biomarker-guided clinical decision-making, illustrating the growing complexity of personalized management in indolent B-cell malignancies.

The clinical application of innovative immunotherapy is illustrated in “Relapsed or refractory central nervous system lymphoma successfully treated by glofitamab combined with lenalidomide.” This report describes encouraging clinical outcomes following treatment with the CD20×CD3 bispecific antibody glofitamab in combination with the immunomodulatory agent lenalidomide. Central nervous system lymphoma remains particularly difficult to treat after relapse, and effective chemotherapy-free strategies are urgently needed. Although based on limited clinical experience, the favorable response demonstrates the promise of combining immune-engaging therapies with immunomodulatory agents to achieve durable disease control while potentially reducing treatment-associated toxicity. The findings contribute valuable preliminary evidence supporting future clinical evaluation of bispecific antibody-based combination therapeutic strategies.

Treatment resistance remains one of the greatest barriers to successful targeted therapy. The mini-review “Mechanisms of kinase inhibitor resistance in subtypes of cutaneous T-cell lymphomas” provides a comprehensive overview of molecular pathways responsible for resistance to kinase inhibitors. The authors describe how genetic mutations, activation of compensatory signaling pathways, epigenetic alterations, and changes within the tumor microenvironment collectively contribute to therapeutic failure. Importantly, the review emphasizes that understanding resistance mechanisms is essential for developing rational combination therapies capable of restoring treatment sensitivity. Although focused on cutaneous T-cell lymphoma, the concepts discussed have broad relevance across lymphoma subtypes and highlight resistance biology as an important frontier in precision hematology.

Personalized medicine extends beyond targeted treatment to encompass careful diagnosis and individualized clinical evaluation. The case report “Synchronous mucosa-associated lymphoid tissue lymphoma in a married couple: a case report” describes the rare occurrence of MALT lymphoma developing simultaneously in spouses. While causality cannot be established, the observation raises intriguing questions regarding shared environmental exposures, infectious agents, and other common risk factors that may contribute to lymphoma pathogenesis. The report also emphasizes the importance of comprehensive diagnostic assessment in unusual clinical presentations and illustrates how rare cases may generate hypotheses that stimulate future biological and epidemiological research.

The final contribution, “Baseline Systemic Immune-Inflammation Index and a Novel FLIPI-SII Model Predict POD24 and Long-Term Survival in Grade 1–3a Follicular Lymphoma,” addresses another essential component of personalized medicine: accurate prognostic assessment. By integrating the systemic immune-inflammation index with the established Follicular Lymphoma International Prognostic Index (FLIPI), the investigators propose a novel prognostic model that improves prediction of early disease progression (POD24) and long-term survival. The study demonstrates the value of combining host inflammatory biomarkers with established clinical prognostic factors to refine risk stratification. Improved prediction models may facilitate individualized surveillance strategies, optimize treatment selection, and identify patients who may benefit from earlier therapeutic intervention.

Collectively, the six articles illustrate several overarching themes that define the future direction of lymphoma research (Figure 1). First, molecular characterization is becoming fundamental to clinical decision-making, enabling therapies to be matched to specific biological alterations. Second, immunotherapy continues to expand beyond conventional monoclonal antibodies through the development of immune checkpoint inhibitors, bispecific antibodies, immunomodulatory drugs, and cellular therapies. Third, understanding the biological mechanisms responsible for therapeutic resistance remains essential for designing more durable treatment strategies. Finally, advances in prognostic biomarkers and predictive models are improving clinicians’ ability to individualize treatment and follow-up according to patient-specific risk.

Although substantial progress has been achieved, significant challenges remain before fully personalized treatment becomes routine clinical practice. Many promising molecular targets require validation in prospective multicenter studies, while predictive biomarkers must demonstrate reproducibility across diverse patient populations. Continued collaboration between basic scientists, translational investigators, and clinicians will be essential to translate laboratory discoveries into meaningful clinical benefit. Integration of comprehensive molecular profiling, multi-omic technologies, artificial intelligence, and biomarker-driven clinical trial designs will further accelerate progress toward truly individualized lymphoma care.

In summary, this Research Topic provides a timely overview of contemporary advances in lymphoma biology and personalized therapy. The contributions span fundamental mechanisms of epigenetic regulation, immune modulation, therapeutic resistance, innovative immunotherapies, prognostic biomarker development, and rare clinical observations that broaden our understanding of lymphoma pathogenesis. Together, these studies reinforce the importance of integrating molecular insights with clinical innovation to improve patient care. As precision hematology continues to evolve, the identification of novel molecular targets, validated biomarkers, and effective combination therapies will be instrumental in achieving more durable responses and better outcomes for patients with low-grade non-Hodgkin lymphoma.

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Footnotes

Edited and reviewed by: Stefano Molica, Hull University Teaching Hospitals NHS Trust, United Kingdom