Leukemia is a malignant tumor with a high recurrence rate and poor prognosis for patients. Thus, there is an urgent need to explore new therapeutic targets that play critical roles in leukemogenesis but have little effect on normal hematopoietic cells. Here, we show that RNA binding protein with multiple splicing (RBPMS), which is highly expressed in acute myeloid leukemia (AML) and associated with poor prognosis of AML, plays critical roles in leukemogenesis. Our study shows that inhibition of RBPMS inhibits self-renewal of leukemia-initiating cells (LICs) and leukemia development but has little effect on normal hematopoiesis. Mechanistically, RBPMS recruits the N6-methyladenosine (m6A) reader insulin-like growth factor 2 mRNA binding protein 3 (IGF2BP3), which promotes the stability of the forkhead box O1 (FOXO1) mRNA in an m6A-dependent manner. Moreover, RBPMS contributes to the progression of leukemia by directly binding to FOXO1 and promoting FOXO1-regulated glycolysis. Overexpression of FOXO1 has been shown to reverse RBPMS inhibition-induced phenotypes in both leukemic cells and mouse models. We also designed a specific inhibitor of RBPMS that has therapeutic effects in AML patient-derived xenograft (PDX) models. We therefore highlight RBPMS as a promising drug target for leukemia therapy.

Immune-checkpoint inhibitors benefit a subset of patients with advanced cancer, and the metabolic determinants of response remain unclear. Here, using targeted metabolomics and metagenomics, we profiled 4,336 plasma samples from 1,714 patients across five tumor types and 16 cohorts spanning Europe and North America, longitudinally sampled during five immune-checkpoint inhibitor-based treatment modalities, including fecal microbiota transplantation. A multimodal machine-learning framework integrating 154 metabolites with clinical variables identified five metabolites, age, body mass index and renal function as predictors of 12-month progression-free survival. The model achieved areas under the curve of 0.88 in training and 0.73 in validation cohorts of 105 and 30 patients, respectively and generalized across seven external cohorts. Histidine was a favorable prognostic feature of survival, whereas long-chain fatty acids and succinate were negatively associated with outcome. Histidine supplementation enhanced antitumor immunity in mice. Histidine-rich diets improved progression-free survival in patients lacking dysbiotic microbiome signatures associated with histidine catabolism.

Background:Despite considerable improvement in cancer treatments, brain metastases are still challenging daily practice in oncology. Their biology remains largely unknown with limited data obtained from brain metastatic samples. Here, using metastatic samples of three different cancer types-breast cancer, melanoma and lymphoma-we aimed to identify a common genomic signature related to metastatic localizations in the brain. Methods:Using samples from 133 patients with metastatic breast cancer, melanoma, or lymphoma, laser-microdissection of cancer cells and transciptomic analyzes were performed on 29 brain metastatic samples, and compared to data from 104 extra-cerebral metastases. To obtain murine models of the common brain metastatic signature observed in patients with these three cancer types, in vivo experiments were performed after intracardiac injections of cancer cell lines. Results:Among patients, we identified 23 common genes up-regulated in brain metastases from breast cancer, melanoma, and lymphoma, including KLK6, a serine protease with trypsin-like properties and physiological expression in oligodendrocytes and normal brain endothelial cells. At protein level, KLK6 expression was significantly higher in brain metastases than in extra-cerebral metastases. In particular, KLK6 was not overexpressed in extra-cerebral metastases of patients who developed brain metastases. In murine models of breast cancer, melanoma, and lymphoma brain metastases, we confirmed that KLK6 overexpression was linked to the implantation of cancer cells in the brain. Conclusion:KLK6 overexpression is linked to brain localizations whatever the cancer type, which provides new perspectives for the development of anti-KLK6 therapeutic strategies, pending specific cancer cell targeting to avoid cytotoxicity on normal brain cells.

Importance:Epigenetic dysregulation is associated with the pathogenesis and progression of diffuse large B-cell lymphoma (DLBCL). MYC/BCL2 double-expressor lymphoma (DEL), a distinct population of DLBCL defined by MYC and BCL2 coexpression, refers to poor prognosis after standard rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) immunochemotherapy. Tucidinostat (or chidamide), an oral, selective histone deacetylase inhibitor, has shown promising activity in DEL. Objective:To evaluate efficacy and safety of tucidinostat plus R-CHOP vs R-CHOP alone as first-line treatment for patients with DEL. Design, Setting, and Participants:This randomized, double-blind, placebo-controlled phase 3 trial enrolled patients from May 21, 2020, through July 25, 2022, with follow-up to June 26, 2025. The trial was conducted at 40 study centers in China; a total of 423 eligible patients were enrolled. Interventions:Patients were randomly assigned in a 1:1 ratio to receive oral tucidinostat (20 mg on days 1, 4, 8, and 11 of each 21-day cycle) or matching placebo, plus 6 cycles of R-CHOP. Patients with a complete response after combination therapy received either tucidinostat or placebo maintenance up to 24 weeks. Main Outcomes and Measures:The primary end point was event-free survival. Secondary end points included complete response rate, progression-free survival, disease-free survival, overall survival, and tolerability. Results:Among 423 patients randomized (median age, 63 years; 47.5% male), the median follow-up duration from randomization was 41.3 months. The tucidinostat group demonstrated a 28% lower risk of disease progression, relapse after complete response, death, or initiation of new therapy for residual disease compared with the placebo group (stratified hazard ratio, 0.72 [95% CI, 0.54-0.96]; P = .02), with a 2-year event-free survival rate of 60.3% vs 50.5%, respectively. The complete response rate was 73.0% vs 61.8% (difference, 11.1% [95% CI, 2.3%-20.0%]), respectively. Increased toxicity associated with treatment was observed in the tucidinostat group but generally manageable with supportive care. Conclusions and Relevance:Tucidinostat plus R-CHOP significantly improved event-free survival, with manageable toxicity in patients newly diagnosed with DEL. This trial is the first to demonstrate the benefit of an epigenetic modulator in DLBCL, offering a new first-line therapeutic approach dually targeting MYC and BCL2 oncoprotein for this high-risk population. Trial Registration:ClinicalTrials.gov Identifier: NCT04231448.

Diffuse large B-cell lymphoma (DLBCL) is clinically and genetically heterogeneous. The existence of genetically defined subtypes with therapeutic implications is clear. Additional considerations that are yet to be fully resolved include defining boundaries between discrete classes, relevant molecular data types, and handling of unclassifiable/composite cases. In this review, we juxtapose points of view on the topic from experts in the field, outline practical workflow considerations, and distill lessons from clinical trials. These synthesize experimental design and analytic considerations that inform the development and evaluation of clinically relevant DLBCL subtyping approaches. SIGNIFICANCE:The most meaningful way to stratify DLBCL remains unresolved, and this represents a significant barrier to adopting a precision medicine paradigm.

Chromosome copy number variations are poorly understood drivers of human malignancies. -7/del(7q) is common in acute myeloid leukemia, confers a poor prognosis, and is thought to harbor several tumor suppressors. Previously, we identified the histone methyltransferase KMT2C as a tumor suppressor in this region. Here, through a differentiation CRISPR screen in hematopoietic stem and progenitor cells, we find that the mitochondrial iron transporter ABCB8 is essential for their differentiation. ABCB8 deficiency accelerates leukemogenesis in vivo and disrupts iron homeostasis, reducing cytoplasmic iron availability and impairing iron-dependent enzymes, including the histone demethylase KDM6A. Consequently, ABCB8 loss elevates H3K27me3 levels, repressing differentiation genes in an iron- and KDM6A-dependent manner. Notably, ABCB8 and KMT2C, neighboring genes on 7q, cooperatively regulate H3K27me3 to suppress leukemogenesis. Our findings reveal ABCB8 as a tumor suppressor in -7/del(7q) acute myeloid leukemia and uncover an epigenetic collaboration between neighboring tumor suppressors, driven by iron-mediated chromatin remodeling.

TBL1XR1 is frequently mutated in diffuse large B-cell lymphoma (DLBCL), yet its functional impact on tumor microenvironment remains poorly defined. In this study, we characterized TBL1XR1 mutations in a cohort of 1842 newly diagnosed DLBCL patients, identifying mutations in 9.4

Glucocorticoids (GCs) are potent immunosuppressive agents that compromise anticancer immune responses, yet the molecular mediators of this effect remain incompletely understood. Here, we identify the acyl-CoA-binding protein/diazepam-binding inhibitor (ACBP/DBI) as a critical effector of the GC-induced suppression of tumor immunosurveillance and immunotherapy efficacy. Using orthotopic murine models of breast cancer, non-small cell lung cancer, and cutaneous fibrosarcoma, we show that corticosterone (CORT) accelerates tumor progression and abrogates therapeutic responses to immunogenic chemotherapy and PD-1 blockade. Genetic ablation or monoclonal antibody (mAb)-mediated neutralization of ACBP/DBI prevents immunosuppression by CORT, restoring both natural and therapy-enhanced antitumor immunity in a T cell-dependent manner. Mechanistically, CORT induces Tsc22d3 expression in dendritic cells, impairs type I interferon signaling, and reduces antigen presentation capacity, which all can be reversed by ACBP/DBI neutralization. The immunosuppressive activity of GCs and the immunostimulatory function of anti-ACBP/DBI mAb converge on Tsc22d3 expression in myeloid cells, as shown by loss-of-function experiments in myeloid-specific Tsc22d3-deficient mice. These findings reveal ACBP/DBI as a central mediator of GC-induced immune evasion and suggest its neutralization as a therapeutic strategy to restore anticancer immunity during endogenous or iatrogenic GC exposure.

Dendritic cells (DCs), the most proficient antigen-presenting cells, bridge innate and adaptive immunity and are critical for anti-cancer immune surveillance. Their function is precisely regulated by protein tyrosine kinases (PTKs), which integrate signals from external stimuli and internal cellular stress to control DC maturation, migration, and antigen presentation. This review systematically synthesizes current knowledge on PTK roles in DC-mediated anti-tumor immunity, with a focused analysis of their differential expression and function across human and mouse DC subsets—including conventional (cDC1, cDC2), plasmacytoid (pDC), and monocyte-derived DCs. We highlight how specific PTK families (e.g., TAM, PDGFR, SRC, JAK) translate pathogen- and damage-associated signals into tailored immune responses. Furthermore, we discuss the dual impact of clinically approved PTK inhibitors on DC function, which can either enhance or suppress anti-tumor immunity depending on context. Finally, we evaluate translational strategies that combine PTK-targeted agents with DC-based vaccines or immune checkpoint blockade, offering a rationale for exploiting PTK-DC crosstalk to develop more effective combinatorial immunotherapies.

Metastatic disease remains the primary cause of cancer mortality, yet the identification of robust therapeutic targets is hampered by tumor heterogeneity and microenvironmental complexity. A key challenge lies in identifying epigenetic regulators that can simultaneously inhibit tumor progression and harness immunity. Here, we leverage single-cell transcriptomics from 120 liver cancer patients to identify E1A-like inhibitor of differentiation 1 (EID1) as the sole histone acetylation regulator upregulated in both tumor cells and effector lymphocytes within metastatic sites. Systemic Eid1 deletion markedly suppresses lung metastasis in melanoma, liver cancer, and breast cancer models. This protection is mediated dominantly by natural killer (NK) cells and type I/II interferons (IFNs), as evidenced by antibody-based cell depletion and cytokine neutralization. Eid1-deficient NK cells exhibit a hyperactivated state with robust proliferation, and their adoptive transfer confers superior metastatic suppression. Notably, Eid1 deficiency augments the accumulation of NK cells and dendritic cells (DCs) in lung metastases and induces a close spatial and transcriptional DC-NK interplay for metastatic defense. Mechanistically, loss of Eid1 upregulates formyl peptide receptor 1 (FPR1) and its ligand annexin A1 (ANXA1) on DCs and NK cells, enabling a FPR1-dependent DC-NK crosstalk that strengthens type I and II IFN responses against tumor dissemination. Conditional knockout demonstrated that intratumoral accumulation of NK cells and DCs is determined by cell-intrinsic Eid1. Critically, targeted Eid1 silencing delivered by nanoparticles significantly enhanced Fpr1 expression and NK activation, eventually suppressing tumor dissemination. Collectively, our study uncovers a previously unrecognized role of EID1 in promoting cancer metastasis by dampening the DC-NK joint immunosurveillance and establishes the therapeutic potential of EID1 inhibition in NK cell transfer and siRNA-based strategies.

Peripheral T-cell lymphoma (PTCL) is an aggressive and heterogeneous lymphoma subtype with high chemoresistance and poor prognosis. Common peripheral blood disease biomarkers with therapeutic potential are lacking. Here, we analyzed the serum metabolic profiles of 557 patients with newly diagnosed PTCL, including 278 extranodal NK/T-cell lymphoma (NKTCL), 117 nodal T-follicular helper cell lymphoma (nTFHL), 92 peripheral T-cell lymphoma, not otherwise specified (PTCL-NOS), 36 ALK positive anaplastic large-cell lymphoma (ALK+ ALCL), and 34 ALK negative ALCL (ALK- ALCL), and identified high free fatty acid (FFA) as an adverse prognostic biomarker across PTCL subtypes. Integrative analysis with transcriptomic and single cell RNA-sequencing datasets further revealed that serum FFA linked to JAK-STAT signaling activation and suppressive tumor microenvironment, characterized by increased infiltration of monocytic myeloid-derived suppressor cells (MDSCs) in NKTCL and M2 macrophages in nTFHL and PTCL-NOS, respectively. Selective JAK1 inhibitor golidocitinib showed pronounced anti-tumor efficacy in the co-culture systems under palmitic acid-induced high FFA conditions and in syngeneic and xenograft murine lymphoma models fed with high-fat diet via the JAK-STAT-IL6/IL10 axis-mediated inhibition of MDSCs in NKTCL and M2 macrophages in nTFHL and PTCL-NOS, respectively. In alignment with our experimental findings, relapsed or refractory PTCL patients with high serum FFA exhibited superior responses to golidocitinib treatment than those with low serum FFA. Collectively, high serum FFA is related to tumor progression and indicates golidocitinib sensitivity, providing novel insights into reprogramming lipid metabolism to dually target the tumor and microenvironment in PTCL.

Diffuse large B-cell lymphoma (DLBCL) is a highly heterogeneous aggressive non-Hodgkin lymphoma. Although the R-CHOP regimen has served as the standard first-line therapy and substantially improved overall survival, its efficacy remains limited in biologically high-risk and treatment-resistant patients, highlighting the intrinsic limitations of uniform treatment strategies. Advances in high-throughput sequencing, single-cell technologies, and spatial profiling have established DLBCL as a collection of distinct molecular subtypes, each characterized by unique pathogenic mechanisms, therapeutic sensitivities, and patterns of resistance evolution. These discoveries have established the foundation for molecular subtype-guided precision therapy. Against this background, the Ruijin Hospital team proposed and implemented the GUIDANCE concept, a molecular classification-guided strategy for targeted therapy combined with chemotherapy. By developing a functional molecular classification system tailored to the Chinese population (LymphPlex) and prospectively matching molecular subtypes with specific targeted agents, the GUIDANCE-01 study significantly improved complete response rates and progression-free survival in newly diagnosed high-risk DLBCL. The GUIDANCE-06 study further demonstrated that this approach could enhance response depth and transplant eligibility in relapsed or refractory DLBCL, while the GUIDANCE-03 study successfully extended the strategy to peripheral T-cell lymphoma, underscoring its cross-lineage applicability. Collectively, these studies establish molecular classification not merely as a biological taxonomy, but as a clinically actionable decision-making framework. Nevertheless, molecular classification represents a static snapshot at a single time point and cannot fully capture dynamic tumor clonal evolution, immune microenvironment remodeling, or treatment-induced selective pressures. To address these limitations, recent efforts have focused on integrating multimodal data-including genomics, transcriptomics, radiomics, tumor microenvironment features, and longitudinal circulating tumor DNA monitoring-into artificial intelligence (AI)-based prognostic and stratification models. Such multimodal AI systems hold the potential to deliver continuous risk assessment and dynamic patient stratification, overcoming the incomplete coverage of conventional molecular subtyping. Looking forward, molecular classification is unlikely to be replaced by AI, but rather will serve as a foundational module within an AI-enabled precision oncology ecosystem. By combining molecular insights with real-time data integration and adaptive decision support, lymphoma management may transition from subtype-guided initial treatment toward comprehensive, longitudinal precision care.

PURPOSE:This study aimed to evaluate the locoregional control in patients with early-stage natural killer/T-cell lymphoma (NKTCL) treated with sandwich chemoradiation therapy. METHODS AND MATERIALS:We performed a post hoc analysis of 87 consecutive patients with early-stage NKTCL enrolled in a prospective, multicenter, randomized phase 3 trial. All participants received standardized treatment comprising 4 cycles of asparaginase-based chemotherapy with integrated radiation therapy. RESULTS:With a median follow-up of 37.9 months, the 3-year survival outcomes of the cohort were overall survival (OS) 87.1%, progression-free survival 84.6%, and locoregional recurrence-free survival 90.8%. Six patients experienced locoregional recurrence, with 4 in the nasal cavity (4.6%), 4 in the nasopharynx (4.6%), and 1 in the cervical lymph node. Recurrence is typically in the radiation field (5 of 6), often in the initial high-standardized uptake value (SUV) region (4 of 6). Radiation therapy-chemotherapy interval (RCI) between 32 and 35 days was associated with improved prognosis, including OS (P = .043), progression-free survival (P = .013), and locoregional recurrence-free survival (P = .007) versus shorter RCI (21-31 days). Quantitative imaging analysis demonstrated that higher mean baseline apparent diffusion coefficient values (≥0.1125 × 10-3 mm²/s) were associated with an improved OS (95.2% vs 71.6%, P = .049). CONCLUSIONS:Asparaginase-based sandwich chemoradiation therapy shows favorable efficacy in early-stage NKTCL, with distinct locoregional recurrence patterns. RCI and apparent diffusion coefficient values emerge as critical prognostic factors, potentially informing treatment optimization.

OBJECTIVE:To explore the clinical features and prognosis of myelodysplastic syndrome with ring sideroblasts (MDS-RS) patients with wild-type splicing factor 3B subunit 1 (SF3B1 ). METHODS:The bone marrow samples from 132 patients with MDS-RS who were initially diagnosed at Shanghai Sixth People's Hospital affiliated to Shanghai Jiao Tong University School of Medicine from January 2009 to February 2021 were collected. Next generation sequencing (NGS)was used to obtain gene mutation information of patients (covering all core mutation genes of MDS), with a particular focus on analyzing the clinical characteristics, co-mutation profiles, and prognosis of MDS-RS patients with wild-type SF3B1 . RESULTS:Among the 132 MDS-RS patients, 50 cases (37.9%) were negative for SF3B1 mutations, of which 39 patients (78%) had concurrent mutations in other genes. The common accompanying mutations were TP53 (15 cases), DNMT3A (10 cases), U2AF1 (8 cases), TET2 (7 cases), ASXL1 (7 cases), and RUNX1 (6 cases), and SETBP1 (3 cases). In the 82 cases (62.1%) who were positive for SF3B1 mutations, the highest occurrence frequency was SF3B1 K700E mutation (42 cases). Additionally, 57 patients (69.51%) had concurrent mutations in other genes, with the top three highest mutation frequencies observed in ASXL1 (13 cases), DNMT3A (11 cases), and RUNX1 (7 cases). Compared to patients with SF3B1 mutations, those with wild-type SF3B1 exhibited significant pancytopenia and higher risk of IPSS-R and IPSS-M prognostic scores. The median overall survival (OS) of patients with wild-type SF3B1 was 22 months, which was significantly shorter than 55 months of SF3B1 mutated patients (P < 0.05), and they also had a higher risk of transformation to acute myeloid leukemia (AML) (P < 0.05). Multivariate analysis revealed that SF3B1 mutation was not an independent prognostic factor affecting MDS-RS, and its prognostic value might be influenced by mutation sites, co-mutations, and other factors. CONCLUSION:Patients with wild-type SF3B1 have a significantly shorter OS compared to those with SF3B1 mutations, and they also have a higher risk of transformation to AML, which may be associated with TP53 mutations.

Diffuse large B-cell lymphoma (DLBCL) patients with 17p deletion (17p-) show variable outcomes under R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) therapy. ALOX15B (arachidonate 15-lipoxygenase type B), located on chromosome 17p, regulates immune responses via arachidonic acid (AA) metabolism. This study investigates its role in DLBCL progression and explores its epigenetic regulation and therapeutic potential. We analyzed bulk and single-cell transcriptomic data from DLBCL cohorts to evaluate ALOX15B expression and its correlation with clinical outcomes, immune microenvironment, and therapy resistance. Functional assays using siRNA knockdown, luciferase reporter, and drug sensitivity experiments were performed in DLBCL cell lines. Murine and patient-derived xenograft (PDX) models were employed to assess tumor behavior and treatment efficacy in vivo. Chromatin immunoprecipitation sequencing (ChIP-seq), assay for transposase-accessible chromatin using sequencing (ATAC-seq), were conducted to explore the epigenetic regulation of ALOX15B. Low ALOX15B expression was associated with inferior progression-free survival (PFS), immunosuppressive microenvironment, and reduced CD8 + T cell cytotoxicity in DLBCL. Mechanistically, ALOX15B deficiency led to upregulation of COX-2/PGE2 signaling and downregulation of the TAP1/MHC-I antigen presentation axis. Silencing ALOX15B promoted tumor cell proliferation and resistance to doxorubicin. Epigenetically, HDAC1/2 were enriched at the ALOX15B promoter region, repressing its expression. Treatment with the HDAC inhibitor tucidinostat restored ALOX15B expression, enhanced tumor cell apoptosis, reinstated antigen presentation, and reprogrammed the tumor immune landscape in both cell lines and in vivo models. ALOX15B is a key epigenetically regulated gene in DLBCL that modulates the tumor immune microenvironment and response to chemotherapy. Its downregulation promotes immune evasion and treatment resistance, while tucidinostat effectively restores its expression and anti-tumor immunity. These findings highlight ALOX15B as a prognostic biomarker and therapeutic target, particularly in 17p− DLBCL.

Epstein-Barr virus (EBV) is a ubiquitous human γ-herpesvirus associated with a wide spectrum of diseases, ranging from autoimmune diseases to malignancies. Recognized as the first human oncogenic virus, multifaceted pathogenesis of EBV-associated diseases has been extensively explored. However, recent evidence suggests that EBV modulates immune cell function to influence the initiation and progression of associated diseases. Expressing a diverse repertoire of viral RNAs and proteins, EBV not only maintains latency with multiple immune evasion mechanisms, but also modulates host cell biology and sculpts a disease-specific immune microenvironment through dynamic interactions with various immune cells like T cells, B cells, macrophages, natural killer cells, and dendritic cells. Correspondingly, an increasing number of immunotherapies targeted T cells, B cells and virus itself have been developed for improved efficacy, including monoclonal antibodies, chimeric antigen receptor T cell (CAR-T) therapy, vaccines, and lytic induction strategies. In this review, regulatory roles of EBV in modulating the immune microenvironment in different context of disease and emerging therapeutic strategies targeted the underlying molecular mechanisms have been systematically discussed. Future research should aim to elucidate the precise molecular pathways involved, identify key therapeutic targets, characterize intra- and inter-tumor heterogeneity, and develop virus-directed strategies to fundamentally counteract EBV-induced immunopathogenic effects.

Extranodal NK/T-cell lymphoma (ENKTL) is an aggressive Epstein-Barr virus (EBV)-associated malignancy with a heterogeneous tumor microenvironment, yet macrophage heterogeneity and tumor-macrophage crosstalk remain poorly defined. Here, we integrate spatial transcriptomic and proteomic profiling with single-cell spatial molecular imaging of ENKTL samples and identify two subgroups defined by distinct macrophage programs. Subgroup 1 is enriched for inflammatory macrophages exhibiting IFN-α/γ responses and immune-regulatory molecules including IDO1 and CD274, whereas Subgroup 2 is immune-quiescent and macrophage-sparse, with its macrophage compartment skewed towards STAB1 macrophages with scavenging features. Notably, an NF-κB-activated and EBV-associated tumor subset is specifically enriched in Subgroup 1, displaying concurrent immunostimulatory and immunoregulatory features that parallel the co-enriched myeloid states and showing reproducible sample-level associations with these myeloid states across datasets. Spatial neighborhood analysis further delineates an inflammation niche where NF-κB tumor cells physically co-localize with these inflammatory macrophages, accompanied by enhanced tumor-myeloid and myeloid-myeloid signaling, implicating a process of tumor-associated myeloid recruitment followed by CCL- and IL1-mediated myeloid self-reinforcement. Critically, higher abundance of this niche correlates with improved survival across independent cohorts, revealing contrasting spatial tumor-immune architectures with prognostic relevance. Together, our study provides a spatially resolved framework for understanding ENKTL biology and guiding immunotherapeutic strategies.

ABSTRACT:The treatment paradigm for lymphoma, a highly heterogeneous group of hematologic malignancies, has been revolutionized by the development of therapies targeting oncogenic signaling pathways. This shift from conventional chemotherapy to precision medicine is driven by a deep molecular understanding of the pathways that govern lymphoma cell survival and proliferation. This review comprehensively surveys the landscape of these targeted therapies, from fundamental molecular mechanisms to clinical breakthroughs. We first dissect the molecular architecture of key oncogenic drivers, covering foundational survival networks such as the B-cell receptor, phosphatidylinositol 3-kinase /protein kinase B/mammalian target of rapamycin, Janus kinase/signal transducer and activator of transcription, and B-cell lymphoma 2 apoptosis pathways; critical regulatory processes like nuclear export controlled by exportin 1 and epigenetic patterns. For each therapeutic class, we discuss the clinical development of specific inhibitors and the challenge of acquired resistance. Furthermore, we examine emerging concepts in lymphoma, including the context-dependent role of the cyclic guanosine monophosphate-adenosine monophosphate synthase-stimulator of interferon genes pathway, to provide a comprehensive overview of the current therapeutic landscape. A central theme of this review is the integration of these targeted agents into clinical practice. We discuss how the successful targeting of oncogenic signaling pathways has enabled the development of effective chemotherapy-free regimens, which offer durable responses with reduced toxicity and improved quality of life. Although initially transformative for patients with indolent lymphomas or those unfit for intensive chemotherapy, this paradigm is now extending to aggressive lymphomas as well. Another pivotal advance is the use of molecular subtyping and predictive biomarkers to guide treatment. As powerfully demonstrated by recent clinical trials, aligning targeted agents with the specific signaling or epigenetic dependencies of a tumor subtype can significantly enhance the efficacy of standard immunochemotherapy backbones in both B-cell and T-cell lymphomas. Finally, we address the persistent challenges of acquired resistance and discuss future directions, including the development of next-generation agents such as proteolysis-targeting chimeras, the design of rational, synergistic combination strategies, and the leveraging of multiomics and artificial intelligence to decipher complex signaling networks. By continuing to translate molecular insights into clinical practice, the field is steadily moving toward the goal of achieving precision cures for patients with lymphoma.