Editorial: Precision Immunotherapy and Novel Target Discovery in Hematological Malignancy

Beibei Zhang^1*Tuoen Liu^2*Yu Pan^3*

• ¹Yunnan University, Kunming, China
• ²West Virginia School of Osteopathic Medicine, Lewisburg, United States
• ³Macau University of Science and Technology, Taipa, Macao, SAR China

Hematological malignancies, encompassing lymphoid and myeloid lineage disorders, exhibit profound molecular heterogeneity that complicates therapeutic interventions. The advent of precision immunotherapy, closely associated with discovery of novel targets and neoantigens, has revolutionized treatment paradigms. The landscape of hematologic malignancy treatment has undergone a paradigm shift with the emergence of precision immunotherapy. This approach leverages molecular insights to design targeted interventions that overcome the immunosuppressive tumor microenvironment (TME) and tumor heterogeneity, which are key barriers to durable remission. Recent advances span novel antigen discovery, engineered cell therapies, biomarker-driven patient stratification, and combinatorial regimens that amplify immune activation while mitigating resistance. This Research Topic highlights recent advances in precision immunotherapy and novel target discovery in hematologic malignancies. As Research Topic Editors, it was our great pleasure to curate and review a number of interesting manuscripts in which cover a wide range of target discovery, immunotherapeutic engineering, and clinical translation. This editorial synthesizes groundbreaking studies illuminating these frontiers, highlighting how mechanistic insights translate to clinical innovation. The following sections dissect pivotal developments in target identification, therapeutic engineering, resistance management, and potential clinical translation, culminating in a roadmap for future precision immunotherapy in hematologic oncology. (1) Novel Target Identification and Validation. Identified as an immune checkpoint upregulated in hematological malignancies, Fan et al. summarized that siglec15 remodels TME by suppressing T lymphocyte activation and proliferation, thereby facilitating malignant cell immune escape infiltration and cytotoxicity including in blood system diseases. Preclinical data support its role in immunotherapy resistance, positioning it as a promising target for immunotherapies. In acute myeloid leukemia (AML), Yan et al. reported that FLT3-ITD mutations drive immune evasion by upregulating checkpoint CD80 via reactive oxygen species (ROS). This mechanistic link between oncogenic signaling and immune suppression suggests dual FLT3/CD80 targeting as a strategy to overcome resistance. Furthermore, Rücker-Braun et al. illustrated that HLA-B*40:01 and HLA-C*03:04 significantly underrepresented in NPM1-mutated AML in a large HLA association study, which was closely correlated with the neoepitopes presented by these HLA alleles that trigger T-cell responses, underscoring the role of immunogenetics in defining responsive patient subgroups. In addition, Zhang et al. provided a mechanistic insight how histone deacetylases (HDACs) remodel the TME by altering chromatin accessibility, condensation and gene transcriptional expression, which plays pivotal roles in regulating physiological processes, cellular fate determination, and the pathogenesis of diseases including hematological malignancy.The authors systematically elaborated on the multidimensional regulatory networks of HDACs and assessed the clinical translation progress and prospects of HDAC inhibitors (HDACis), as novel epigenetic-targeted therapeutic agents, in future precision medicine. (2) Innovative Immunotherapeutic Platforms. CAR cell exhaustion is a major cause of relapse. Guo et al. performed an integrated analysis associated with anti-CD19 CAR-T with epigenetic modulation and their results suggested that incorporating lysine-specific demethylase 1 (LSD1) shRNA into anti-CD19 CAR-T cells improves the efficacy against diffuse large B-cell lymphoma (DLBCL) by reducing T-cell exhaustion and prolonging persistence. In another study, Zhou et al. reported retroviral vector-delivered anti-CD7 CAR-T cells achieved remission in refractory T-cell acute lymphoblastic leukemia (T-ALL), demonstrating its feasibility with the good therapeutic effect and high safety from the clinical observation of a 34-year-old male patient developed multi-line drug resistance after high-intensity chemotherapy. Besides T cells, Natural killer (NK) cells, endowed with spontaneous cytotoxicity against infectious pathogens and cancer cells, also hold significant importance in leukemia treatment. Ye et al. examined the drug, aclacinomycin (ACM), sensitizes AML cells to NK cell killing by inducing increased calreticulin exposure as well as NK cell effector productions like perforin and granzyme B, validating the immunogenic cell death (ICD) as a bridge between chemotherapy and enhanced immunotherapy. (3) Overcoming Resistance and Heterogeneity. Understanding leukemia-associated immunophenotypes (LAIP) may aid in designing therapies to enhance patient outcomes. In one AML study, Gémes et al. systematically explored multiplex immunophenotyping of AML via single-cell profiling, revealing therapy-resistant subpopulations with distinct markers. Such heterogeneity underscores the need for combinatorial targeting to eliminate residual disease. This research highlights the potential of single-cell LAIP profiling and immune mediator measurements for monitoring treatment responses, identifying measurable residual disease, and detecting therapy-resistant cell populations in AML. In addition, Li et al. reported single nucleotide polymorphisms (SNPs) in immune-related gene impact AML treatment response and survival, advocating for personalized immunogenomic screening. Their findings regarded the associations between AML and SNPs in genes including HMOX1, TXNIP, TNSF10/TRAIL, etc. and found TNFAIP2 genes serve as a critical basis for forecasting treatment responses and prognostic outcomes in AML patients. For other hematological malignancies, Wang et al. conducted an integrated review with the aim of summarizing and analyzing the latest research advances in primary large B-cell lymphomas occurring in immune-privileged sites (IP-LBCLs), with a particular focus on emerging treatment strategies in the era of targeted therapy and immunotherapy. Moreover, in another clinical outcome observation, Wang et al. demonstrated that the orelabrutinib, lenalidomide plus sintilimab achieved durable responses and a manageable safety profile in their relapsed/refractory (R/R) DLBCL patients probably by the immune associated TME remodeling. (4) Clinical Translation and Biomarker-Driven Therapy. As the drug repurposing, Hu et al. examined fostamatinib, a SYK inhibitor for chronic immune thrombocytopenia (ITP) treatment, exhibits dual cytotoxicity and immune checkpoint modulation in leukemia models, supporting its repositioning for hematologic malignancies. Shan et al. performed analyses to identify the hub genes and immune-related pathways in AML to provide new theories for immunotherapy by the bioinformatics-guided target discovery. The findings revealed Complement Factor D (CFD) as a highly expressed hub gene with a positive correlation to IL-2, which in turn exhibits positive associations with CD27 on CD24⁺CD27⁺ B cells, along with the JAK/STAT and PI3K/AKT signaling pathways, all three of which are positively linked to AML initiation and progression. Their additional experiments were conducted to further validate and enhance the reliability of the hub gene, as well as its physiological functions and those of its associated immune-related pathways. In addition, Li et al. conducted an analysis combining a case report with a review of relevant literature on primary seminal vesicle diffuse large B-cell lymphoma. Their work highlights the diagnostic challenges associated with this condition and emphasizes the need for increased clinical vigilance and definitive pathological examination in managing primary seminal vesicle lymphoma. Interestingly, Liang et al. recently developed a technique that distinguishes DLBCL from CLL using Raman spectroscopy combined with bioinformatics-based identification of key genes and pathways, enabling rapid diagnostic classification. The established set of molecular markers can facilitate patient diagnosis and prognostic evaluation, providing a valuable foundation for precision therapeutic applications. Precision immunotherapy in hematologic malignancies is rapidly evolving from target discovery to engineered solutions. By dissecting immune evasion mechanisms and leveraging cutting-edge technologies (e.g., AI-driven neoantigen prediction, precision diagnosis), recent studies provide a roadmap for next-generation therapies. Future success hinges on integrating multi-omics data, optimizing combinatorial regimens, and validating biomarkers in prospective trials.