Multiple myeloma (MM) is a malignant hematological disorder characterized by the neoplastic proliferation of plasma cells. Hypercalcemia is a common complication in MM and is often considered a secondary consequence of disease progression. When calcium levels are severely elevated, it can lead to coma in affected patients. However, whether hypercalcemia plays a direct role in MM progression remains unclear. Herein we found that high calcium concentrations promote MM cell proliferation and it was associated with calpain-2 (CAPN2). We also observed that CAPN2 expression is significantly increased in MM patients and correlates with poor prognosis. Furthermore, knockdown of CAPN2 inhibited MM cell proliferation both in vitro and in vivo via upregulation of FN14 and induction of apoptosis. Importantly, treatment with ALLN, a CAPN2 inhibitor, substantially suppressed MM cell proliferation in vitro and in vivo by inducing apoptosis. Notably, ALLN significantly enhanced the sensitivity of MM cells to commonly used clinical drugs bortezomib and doxorubicin, while exhibiting no obvious cytotoxicity in normal cells. These findings establish CAPN2 as a promising therapeutic target in MM, with its inhibitor serving as a potential lead compound for further clinical evaluation. Our study also elucidates the relationship between hypercalcemia, CAPN2, and malignant proliferation in MM cells, and expands the therapeutic landscape for MM patients.

Diffuse large B-cell lymphoma (DLBCL) remains a therapeutic challenge, with a substantial proportion of patients failing to respond to standard regimens. Natural biflavonoids have demonstrated antitumor potential, but their effects on the metabolic vulnerabilities of DLBCL are poorly understood. This study aimed to elucidate the antitumor efficacy and of pulvinatabiflavone (PUF), a novel biflavonoid monomer isolated from Selaginella cuspidata, against DLBCL and the related mechanism. The antiproliferative effects of PUF were evaluated in multiple DLBCL cell lines (OCI-LY8, SU-DHL-2, SU-DHL-8, and RIVA) and a xenograft mouse model using CCK-8, flow cytometry (apoptosis/cell cycle), and Western blotting. Metabolomics, transcriptomics, functional rescue experiments (with IMP and dGTP), and SLC25A15 knockdown models were used to investigate the mechanism of PUF. PUF potently inhibited DLBCL cell proliferation (IC₅₀ < 2 μg/ml at 48 h), induced apoptosis, and caused G2/M cell cycle arrest. Multiomics analyses revealed that PUF disrupted purine nucleotide metabolism, leading to critical dGTP depletion and subsequent DNA damage, as evidenced by increased γ-H2AX expression. This DNA damage was ameliorated by supplementation with the purine metabolites IMP or dGTP. PUF was found to downregulate the mitochondrial transporter SLC25A15, which is highly expressed in DLBCL. Molecular docking and cellular thermal shift assay (CETSA) confirmed that PUF directly binds to the mitochondrial transporter SLC25A15. Knockdown of SLC25A15 ameliorated the DNA damage phenotype, which was similarly rescued by dGTP. Importantly, in the xenograft model, PUF treatment not only suppressed tumor growth but also downregulated SLC25A15 and upregulated γ-H2AX in tumor tissues, confirming the mechanism in vivo. The biflavonoid PUF exerts profound anti-DLBCL effects by directly targeting SLC25A15, disrupting purine nucleotide metabolism, thereby inducing dGTP shortage-mediated DNA damage. Our integrated findings from in silico, cellular, and animal models suggest that PUF is a promising therapeutic candidate and reveal that SLC25A15 is a novel metabolic target in DLBCL.

Multiple myeloma (MM) is a hematologic malignancy characterized by clonal proliferation of malignant plasma cells. While proteasome inhibitors and novel immunotherapies have markedly shifted the clinical trajectory of multiple myeloma, the persistence of therapeutic resistance and disease recurrence remains a formidable challenge. Metabolic reprogramming has emerged as a critical functional layer driving MM progression and drug resistance. It extends beyond mere energetic anomalies, integrating genetic context, bone marrow microenvironmental stress, and therapeutic selection pressure into a dynamic, systemic adaptive network. This review aims to systematically elucidate the molecular mechanisms underlying the rewiring of major metabolic pathways in MM, including the aberrant activation and interaction of glucose, lipid, amino acid, nucleotide, and trace element (iron/copper) metabolism. It also explores the role of the gut microbiota as a distal regulator influencing disease progression through its metabolites. Collectively, these pathways constitute an interconnected metabolic network that sustains tumor proliferation, stress adaptation, immune evasion, and drug resistance. Furthermore, it discusses how metabolic states encode functional information largely invisible to conventional staging systems, thereby positioning metabolic vulnerabilities as conditional therapeutic targets and a complementary layer for biomarker development, risk stratification, and treatment selection in MM. In conclusion, this framework establishes a conceptual and translational reference, defining stress-adaptive metabolic states as actionable biological insight guiding metabolism-informed therapeutic and biomarker strategies in multiple myeloma.

The Warburg effect states that cancer cells preferentially undergo aerobic glycolysis, producing lactate as a key metabolic byproduct. Lactate acidifies the tumor microenvironment (TME) and serves as a signaling molecule and substrate for lysine lactylation (Kla), a novel posttranslational modification (PTM) discovered in 2019 that links glycolytic metabolism to epigenetic and proteomic reprogramming. The reversible modification of histones and nonhistone proteins orchestrates oncogenic adaptation and drives tumor progression. However, gaps persist in our understanding of the multifactorial regulation of lactylation and its translational potential in overcoming tumor heterogeneity and resistance. This review highlights the emerging roles of lactylation in cancer therapies, including the enhancement of DNA repair mechanisms during chemotherapy, stabilization of key signaling effectors upon targeted therapy, and promotion of an immunosuppressive TME in immunotherapy. We further examined regulatory factors associated with lactylation, from competitive PTMs and genetic mutations to microbial influences and environmental signals. Additionally, we discuss the therapeutic potential of targeting lactylation via indirect modulators currently under investigation and the visualization of lactate and lactylation modifications. By synthesizing these insights, this review highlights lactylation as a reversible metabolic-epigenetic axis for precision oncology, enabling predictive biomarkers, combination strategies, and novel interventions to address the dynamic challenges of cancer.

Mantle cell lymphoma (MCL) is an aggressive subtype of B-cell non-Hodgkin’s lymphoma. The applicability of circulating tumor DNA (ctDNA) for predicting treatment response and prognosis in MCL remains underexplored. This study included 34 MCL patients receiving first-line chemoimmunotherapy. We assessed the ability of plasma ctDNA to detect tumor-specific genetic alterations and explored its potential as a noninvasive biomarker for treatment response and prognosis in MCL. Commonly mutated genes in MCL included CCND1 (93.5

Mantle cell lymphoma (MCL) exhibits significant biological and clinical heterogeneity, necessitating a refined prognostic model. According to the drawbacks of existing models which do not truly define the complexity of the disease, we used the clinical and molecular data from nine medical centers of China to validate the predictive utility of progression of disease within 24 months (POD24), and also established a novel prognostic risk model to predict the survival outcome of MCL patients. POD24 occurred in 37.7% of evaluable patients, with the median over survival being 21 months (vs. 122 months for those without POD24, P < 0.0001). The POD24-based risk model had the highest sensitivity to predict survival with the most satisfying AUC value for risk score (AUC = 0.869). In conclusion, we confirm the obviously predictive performance of POD24 and established a novel risk model combined POD24 and clinical factors. Our new prognostic model might be helpful in effectively classify MCL patients with high-risk groups in terms of survival rate, which may help in selecting high-risk MCL patients for more intensive treatment at time of relapse.

Drug resistance is one of the main reasons for cancer treatment failure, leading to a rapid recurrence/disease progression of the cancer. Recently, artificial intelligence (AI) has empowered physicians to use its powerful data processing and pattern recognition capabilities to extract and mine valuable drug resistance information from large amounts of clinical or omics data, to study drug resistance mechanisms, to evaluate and predict drug resistance, and to develop innovative therapeutic strategies to reduce drug resistance. In this review, we proposed a feasible workflow for incorporating AI into tumor drug resistance research, highlighted current AI-driven tumor drug resistance applications, and discussed the opportunities and challenges encountered in the process. Based on a comprehensive literature analysis, we systematically summarized the role of AI in tumor drug resistance research, including drug development, resistance mechanism elucidation, drug sensitivity prediction, combination therapy optimization, resistance phenotype identification, and clinical biomarker discovery. With the continuous advancement of AI technology and rigorous validation of clinical data, AI models are expected to fuel the development of precision oncology by improving efficacy, guiding therapeutic decisions, and optimizing patient prognosis. In summary, by leveraging clinical and omics data, AI models are expected to pioneer new therapy strategies to mitigate tumor drug resistance, improve efficacy and patient survival, and provide novel perspectives and tools for oncology treatment.

Central nervous system (CNS) relapse in patients with diffuse large B-cell lymphoma (DLBCL) confers a dismal prognosis. Controversy exists regarding the optimal method of CNS prophylaxis in high-risk DLBCL. Although methotrexate (MTX) is the most widely used therapy for CNS prophylaxis, results from previous studies investigating systemic high-dose methotrexate or intrathecal methotrexate remain inconclusive. Therefore, additional strategies for preventing CNS relapse in DLBCL patients are required. We evaluated the efficacy and safety of different prophylactic regimens: thiotepa plus high-dose methotrexate (TT-HD-MTX), high-dose methotrexate (HD-MTX), or intrathecal methotrexate and cytarabine (IT) in newly diagnosed DLBCL patients with high-risk for CNS relapse. We retrospectively analyzed all newly diagnosed DLBCL patients with high risk for CNS relapse (CNS risk score 4-6, CD5 positive, primary cutaneous DLBCL-leg type, or involvement of kidney, adrenal gland, breast, uterus, sinuses, or testicles) treated at Hunan Cancer Hospital between November 2009 and August 2024. Patients received either TT-HD-MTX (thiotepa 40 mg/m2, methotrexate 3.5 g/m2 for 2 cycles after the course of treatment), HD-MTX (methotrexate 3.5 g/m2 for 2 cycles after the course of treatment), or IT prophylaxis (4 doses during the course of treatment). The primary endpoint was the cumulative incidence of CNS relapse at 2 years, and the secondary endpoint was adverse events. A total of 245 newly diagnosed DLBCL patients (132 males; median age 60 years, range 19-76) with high-risk for CNS relapse were included. Of these, 173 patients were stage Ⅲ-Ⅳ disease, 36 had kidney or adrenal gland involvement, and 46 were CD5 positive. With a median follow-up of 30 months, the cumulative incidence of CNS relapse at 2 years was 16.7% (14/84) in the IT group, 10.0% (11/110) in the HD-MTX group, and 3.9% (2/51) in the TT-HD-MTX group. After multiple comparisons correction, no significant difference was observed between the IT and HD-MTX groups (P = 0.644). However, significant differences were observed between the TT-HD-MTX and HD-MTX groups (P = 0.0003), as well as between the TT-HD-MTX and IT groups (P = 0.0002). The most common adverse events included leukopenia (17.9% in the IT group, 50.9% in the HD-MTX group, and 52.9% in the TT-HD-MTX group), thrombocytopenia (14.3% in the IT group, 31.8% in the HD-MTX group, and 35.3% in the TT-HD-MTX group), and anemia (11.9% in the IT group, 27.3% in the HD-MTX group, and 29.4% in the TT-HD-MTX group). Grade 3-4 adverse events included leukopenia (2.4% in the IT group, 9.1% in the HD-MTX group, and 9.8% in the TT-HD-MTX group), thrombocytopenia (1.2% in the IT group, 4.5% in the HD-MTX group, and 5.9% in the TT-HD-MTX group), and pneumonia (2.4% in the IT group, 3.6% in the HD-MTX group, and 3.9% in the TT-HD-MTX group). No treatment-related deaths were reported. Thiotepa plus high-dose methotrexate is an effective and well-tolerated CNS prophylactic regimen for high-risk newly diagnosed DLBCL patients. We are currently conducting prospective studies to validate these findings. Central nervous system prophylaxis; Diffuse large B-cell lymphoma; Thiotepa; High-dose methotrexate.

Mantle cell lymphoma (MCL) is an aggressive subtype of B-cell non-Hodgkin’s lymphoma. While plasma circulating tumor DNA (ctDNA) has demonstrated diagnostic and prognostic value in diffuse large B-cell lymphoma and Hodgkin lymphoma, its significance in MCL remains unclear. This study analyzed paired treatment-naïve plasma and tissue samples from 34 MCL patients with response data after first-line chemotherapy, targeting 475 genes associated with hematopoietic and lymphoid neoplasms. We assessed the ability of plasma ctDNA to detect tumor-specific genetic alterations and explored its potential as a non-invasive biomarker for predicting treatment response and prognosis. The most frequently mutated genes in baseline tissues were CCND1 (93.5%), ATM (48.4%), KMT2D (25.8%), and TP53 (25.8%). Subgroup analysis showed that genetic alterations in CDKN2A (P=0.028), along with those in the B cell antigen receptor (BCR) and endosomal Toll-like receptor (TCR) signaling (P=0.004), as well as the PI3K pathway (P=0.008), were significantly enriched in the blastoid type of MCL. ATM mutations (P=0.041) were more prevalent in patients with low scores on the Mantle Cell Lymphoma International Prognostic Index (MIPI), while epigenetic chromatin remodeling pathway alterations (P=0.028) were more common in MIPI-high patients. Plasma ctDNA detected 66.3% (118/178) of tissue-based somatic variants, yielding an overall detection sensitivity of 73.3%. The highest sensitivity was observed for structural variants (96.6%), followed by mutations/indels (71.3%) and copy number variants (30.0%). At the patient level, 75% (21/28) of patients with paired tissue and plasma samples exhibited moderate to almost perfect agreement in detecting genomic variants in panel-targetable genes, achieving a kappa coefficient ≥ 0.6. Pretreatment ctDNA levels were highly specific for predicting treatment response (100%), although the sensitivity was suboptimal at 68.2%. Higher ctDNA levels were independently associated with shorter progression-free survival (PFS; P=0.002) and overall survival (OS; P=0.009). Additional genetic features associated with shorter PFS included mutations in TP53 (P=0.002), SMARCA4 (P=0.023), and TRAF2 (P=0.023). Furthermore, mutations in TP53 (P=0.006) and TERT (P=0.031) in baseline plasma ctDNA were predictive of reduced OS. Plasma ctDNA serves as a noninvasive approach for detecting tumor-derived genetic aberrations associated with treatment response and survival outcomes in MCL. These findings underscore its clinical utility for diagnosis, recurrence prediction, and surveillance monitoring in MCL. Zhou Ouyang, Ruolan Zeng, Song Wang, Xiaoying Wu, Yajun Li, Yizi He, Caiqin Wang, Chen Xia, Qiuxiang Ou, Wei Yang, Ling Xiao, Hui Zhou. Noninvasive tumor genetic profiling and disease surveillance in mantle cell lymphoma via plasma circulating tumor DNA [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 5897.

Immunotherapy with programmed cell death 1 ligand 1 (PD-L1) blockade was effective in patients with NK/T-cell lymphoma. In addition to PD-L1, indoleamine 2,3-dioxygenase-1 (IDO1) is one of the most promising immunotherapeutic targets. High proportions of PD-L1 and IDO1 proteins were observed by immunohistochemistry (IHC) from 230 newly diagnosed patients with NK/T lymphoma with tissue samples from three cancer centers and were associated with poor overall survival (OS) in patients with NK/T lymphoma. Importantly, the coexpression of PD-L1 and IDO1 was related to poor OS and short restricted mean survival time in patients with NK/T lymphoma and was an independent prognostic factor in the training cohorts, and which was also validated in 58 NK/T lymphoma patients (GSE90597). Moreover, a nomogram model constructed with PD-L1 and IDO1 expression together with age could provide concise and precise predictions of OS rates and median survival time. The high-risk group in the nomogram model had a positive correlation with CD4 + T-cell infiltration in the validation cohort, as did the immunosuppressive factor level. Therefore, high PD-L1 and IDO1 expression was associated with poor OS in patients with NK/T lymphoma. PD-L1 and IDO1 might be potential targets for future immune checkpoint blockade (ICB) therapy for NK/T lymphoma.

Background: Central nervous system (CNS) relapse in patients with diffuse large B-cell lymphoma (DLBCL) results in dismal prognosis. There is controversy over the treatment method and efficacy of CNS prophylaxis in high risk DLBCL. Although methotrexate (MTX) is the most widely used therapy for CNS prophylaxis, results from previous studies investigating the optimal regimen for CNS prophylaxis remains unclear. Therefore, additional strategies for preventing CNS relapse in DLBCL patients are required. We evaluated the efficacy and safety of different prophylactic regimens (thiotepa plus high-dose methotrexate, high-dose methotrexate alone or intrathecal methotrexate and cytarabine) in newly diagnosed DLBCL patients with high-risk for CNS relapse. Methods: We retrospectively analyzed records of all newly diagnosed DLBCL patients at high risk for CNS relapse treated at Hunan Cancer Hospital between November 2009 and January 2024. Patients received either thiotepa plus high-dose methotrexate (thiotepa 40mg/ m2, methotrexate 3.5g/m2, T-HD-MTX), high-dose methotrexate alone (methotrexate 3.5g/m2, HD-MTX), or intrathecal methotrexate and cytarabine (IT). The primary endpoint was the rate of CNS relapse, and the secondary endpoints included progression-free survival (PFS) and adverse events (AEs). Results: 232 newly diagnosed DLBCL patients (128 males; median age 59 years, range, 19-76) with high-risk for CNS relapse was included in this study, of whom 170 patients were Ⅲ-Ⅳ stage, 136 patients were non-GCB and 46 patients were CD5 positive. Prophylactic regimens were as follows: IT MTX in 84 patients (36.2%), HD-MTX in 105 patients (45.3%), and T-HD-MTX in 43 patients (18.5%). With a median follow-up of 43 months, CNS relapse rate was 22.6% (19/84) in IT group, 8.6% (9/105) in HD-MTX group, 2.3% (1/43) in T-HD-MTX group (P＜0.001). The most common AEs were leukopenia (56.5%), thrombocytopenia (32.8%), and anemia (37.5%). Grade 3-4 AEs included leukopenia (10.8%), thrombocytopenia (2.2%), and pneumonia (3.4%), and no severe AEs reported. Conclusion: Thiotepa plus high-dose methotrexate is an effective and well-tolerated CNS prophylactic regimen for high-risk newly diagnosed DLBCL patients.

Background Meteorin (METRN) is expressed predominantly in the central nervous system (CNS), where it functions by regulating glial cell differentiation and promoting axonal elongation. Nonetheless, its function within tumors is still not well understood. In this study, we focused on investigating its expression across various cancers and delving deeper into how METRN expression correlates with prognosis and immune infiltration. Methods We explored METRN expression patterns in pan-cancers utilizing data obtained from the UCSC Xena and TCGA. In addition, analyses of survival and clinical association were conducted for tumors where METRN could affect the prognosis. Subsequently, nomogram models were constructed for sarcoma (SARC) and prostate adenocarcinoma (PRAD) to verify METRN's prognostic value in tumors. Furthermore, we also discussed the link between METRN and immune infiltration. As far as mechanisms are concerned, functional enrichment analysis was conducted to analyze the functional components and signaling pathways involved in METRN. Results This study found that METRN was abnormally expressed in various tumors, closely connected with the prognosis and clinical characteristics of several tumors, and had good prognostic value. Moreover, analysis of immune infiltration revealed that METRN interacts with multiple immune cells, with alterations in the immune microenvironment potentially influencing tumor prognosis. Enrichment analysis indicates that METRN may influence tumorigenesis and progression through immune-related pathways. Conclusion To sum up, our study demonstrates that METRN can be a prospective predictive biomarker in diverse cancer types and a promising target for cancer immunotherapy for pan-cancer.

Background: It is well known that long non-coding RNAs (lncRNAs) play a vital role in cancer. We aimed to explore the prognostic value of potential immune-related lncRNAs in hepatocellular carcinoma (HCC). Methods: Validated the established lncRNA signature of 343 patients with HCC from The Cancer Genome Atlas (TCGA) and 81 samples from Gene Expression Omnibus (GEO). Immune-related lncRNAs for HCC prognosis were evaluated using Cox regression and Least Absolute Shrinkage and Selection Operator (LASSO) analyses. LASSO analysis was performed to calculate a risk score formula to explore the difference in overall survival between high- and low-risk groups in TCGA, which was verified using GEO, Gene Ontology (GO), and pathway-enrichment analysis. These analyses were used to identify the function of screened genes and construct a co-expression network of these genes. Results: Using computational difference algorithms and lasso Cox regression analysis, the differentially expressed and survival-related immune-related genes (IRGs) among patients with HCC were established as five novel immune-related lncRNA signatures (AC099850.3, AL031985.3, PRRT3-AS1, AC023157.3, MSC-AS1). Patients in the low‐risk group showed significantly better survival than patients in the high‐risk group ( P = 3.033e−05). The signature identified can be an effective prognostic factor to predict patient survival. The nomogram showed some clinical net benefits predicted by overall survival. In order to explore its underlying mechanism, several methods of enrichment were elucidated using Gene Set Enrichment Analysis. Conclusion: Identifying five immune-related lncRNA signatures has important clinical implications for predicting patient outcome and guiding tailored therapy for patients with HCC with further prospective validation.

Background: Mantle cell lymphoma (MCL) is characterized by significant biological and clinical heterogeneity, necessitating the identification of prognostic biomarkers to guide its management. Circulating tumor DNA (ctDNA) has emerged as an innovative diagnostic and prognostic biomarker in various non-Hodgkin lymphoma subtypes and potentially extending its utility to MCL. The potential application value of ctDNA detecting in mantle cell lymphoma is unclear. Methods: Thirty-eight MCL patients were enrolled in this study. Tissue, plasma, and bone marrow (BM) samples were obtained prior to initiation of first-line therapy for targeted sequencing, which included exons and selected introns of 475 genes associated with leukemia and lymphoma. Post-treatment plasma samples were also obtained from 17 of these patients for subsequent targeted sequencing analysis. Results: In our cohort, the median age was 59 years (range, 37-76), with 10 individuals (26%) being over 65 years. According to the MCL International Prognostic Index (MIPI), 24 patients (63%) were classified as low risk. Clinical characteristics showed that 90% of patients had stage IV disease by the Ann Arbor staging system. Seven patients (18%) exhibited blastoid morphology, and 24 patients (63%) had a Ki-67 proliferation index of ≥30%. BM-flow cytometry (FCM), BM-NGS, and plasma-NGS tests were conducted on all 38 patients, with 33 also undergoing tissue NGS, yielding positive detection rates of 63.2%, 86.8%, 97.4%, and 100%, respectively. The targeted NGS sequencing for BM detection demonstrated 100% sensitivity compared to FCM. Nine patients with negative bone marrow FCM but NGS positive exhibited significantly lower pretreatment plasma ctDNA (Pre-ctDNA) levels and bone marrow mutation abundance. Plasma ctDNA identified mutations with high concordance to tissue results, achieving a 75% sensitivity rate. For the diagnosis-related gene CCND1 and the prognosis-related gene TP53, plasma ctDNA detection sensitivity was 94% and 100%, respectively. Analyses of plasma ctDNA quantification and mutation numbers indicated that higher pre-ctDNA levels and greater mutation numbers were significantly correlated with several adverse clinical factors, such as blastoid morphology, BM involvement, high MIPI risk, extranodal involvement at ≥3 sites, high Ki67 index, and the presence of B symptoms. Notably, higher Pre-ctDNA levels were observed in patients who did not achieve a complete response (CR) after treatment. Gene and signaling pathway analyses of pre-ctDNA revealed that TP53 mutation, CARD11 mutation, and BCR signaling pathway mutation enrichment were significantly associated with a failure to achieve CR post-treatment. Further survival outcome analyses confirmed the negative impact of TP53 mutations and BCR signaling pathway mutation enrichment on long-term survival. Moreover, CDKN2A, ATM, FAT1, PI3K-AKT-mTOR pathway, and MAPK-ERK pathway were identified as unfavorable factors for overall survival (OS). Additionally, elevated pre-ctDNA levels and a higher number of mutations were significantly associated with poor OS (P<0.001 and P=0.005). Comparative analyses of 17 patients with post-treatment plasma samples showed that the log-fold change in ctDNA was significantly lower in patients in remission.. In contrast, two patients with elevated post-treatment plasma ctDNA levels demonstrated inferior progression-free survival (PFS) and OS Conclusion: Targeted NGS-based ctDNA testing represents a highly promising non-invasive approach, with pre-treatment plasma ctDNA exhibiting mutational and quantitative characteristics that significantly enhance the diagnosis and prognostic stratification of MCL. Elevated post-treatment plasma ctDNA levels in patients are indicative of a poor prognosis.

Background: Classical Hodgkin lymphoma (cHL) is highly curable by frontline therapy. However, the search for an effective standard second-line therapy for patients with refractory or relapsed (R/R) cHL continues. Sintilimab, a fully human IgG4 monoclonal antibody targeting the PD-1 receptor, has demonstrated significant efficacy in R/R cHL. This study evaluates the efficacy of sintilimab combined with gemcitabine, cisplatin, and dexamethasone (S-GDP), an economical regimen cost only 600 dollars per cycle, as second-line therapy for R/R cHL. Methods: We conducted a retrospective study including 24 patients with R/R cHL who received S-GDP (gemcitabine, 800 mg/m2, d1,8; cisplatin, 25 mg/m2, d1-3; dexamethasone, 20mg bid, d1-4; sintilimab, 200mg, d8; 21 days/cycle) as second-line therapy from March 2020 to January 2024. After the combination treatment, patients could receive ASCT or RT as consolidation therapy, followed by sintilimab maintenance. The primary endpoint was the best overall response rate (ORR) during the second-line therapy according to the 2014 version of Lugano efficacy evaluation criteria, and the secondary endpoints included complete response (CR), partial response (PR), progression-free survival (PFS), and adverse events (AEs). Results: Twenty-four patients (15 males; median age 34 years, range, 17-55) from 4 institutions with histologically confirmed cHL were included in this retrospective study, of whom 18 patients were Ⅲ-Ⅳ stage, 13 patients were refractory. Fourteen advanced-stage patients (77.8%) had International Prognostic Score (IPS) scores≥3. Six early-stage patients (100%) had unfavorable factors. The median number of treatment cycles was 6 (range 1-8). The ORR and CRR were 83.3% and 62.5%, respectively. In refractory patients, the ORR and CRR were 76.9% and 61.5%, respectively, while in relapsed patients, the ORR and CRR were 90.9% and 63.6%, respectively. With a median follow-up of 45.2 months, the median PFS was 42.5 months for all patients, 45.2 months for refractory patients, 34.2 months for relapsed patients. Among the 24 patients, 11 patients received ASCT with subsequent sintilimab maintenance, 3 patients rejected ASCT as consolidation therapy with only sintilimab maintenance, 1 patient received only RT as consolidation therapy. The most common AEs were leukopenia (91.6%) and anemia (83.3%), with grade 3-4 AEs including leukopenia (20.8%), thrombocytopenia (8.3%), and pneumonia (8.3%). No treatment-related severe AEs or mortality occurred. Conclusion: The S-GDP regimen is an effective, economical, and well-tolerated second-line therapy for R/R cHL, efficiently bridging patients to ASCT and offering a promising alternative for this patient population.

NK/T-cell lymphoma (NKTCL) is a rare type of non-Hodgkin lymphoma (NHL). Although L-asparaginase-based chemotherapy has significantly improved survival in early-stage patients, the prognosis is poor in advanced and relapsed or refractory patients. CD47 is a promising target for cancer immunotherapy. However, the expression of CD47 in NKTCL and the antitumor effect and mechanism of the anti-CD47 monoclonal antibody (mAb) AK117 in NKTCL remain unclear. Firstly, the expression level of CD47 protein in NKTCL cells was detected by immunoblot and flow cytometry. Secondly, in order to validate the role of CD47 downregulation in the proliferation, apoptosis, and cell cycle of NKTCL cells, we used shRNA transfection to knock down CD47 expression. We determined the effect of knocking down CD47 and the novel anti-CD47 antibody AK117 on the phagocytosis of NKYS and YTS cells by M2 macrophages in vitro. Finally, we assessed the ability of AK117 to inhibit tumor growth in an NKTCL xenograft model in which YTS cells were engrafted in SCID mice. The results showed that CD47 is relatively highly expressed in NKTCL cells. CD47 knockdown in NKTCL promoted phagocytosis by M2 macrophages in an in vitro coculture assay. The study also demonstrated that anti-CD47 mAb AK117 promoted phagocytosis of NKTCL cells by M2 macrophages. In addition, in vivo experiments showed that the anti-CD47 mAb AK117 significantly inhibited the growth of subcutaneous xenograft tumors in SCID mice compared to the control antibody IgG. Our results indicate that targeting CD47 monoclonal antibodies is a potential therapeutic strategy for NKTCL.

Background: At present, there is no standardized treatment regimen for early-stage extranodal natural killer/T-cell lymphoma (ENKTL). Induction chemotherapy based on pegaspargase, followed by radiotherapy, often leads to more favorable therapeutic outcomes. However, about 30-40% of patients still do not achieve complete remission (CR), particularly those with high-risk factors. Moreover, these treatment approaches can cause severe myelotoxicity and gastrointestinal toxicity, which subsequently reduce the rate of treatment completion and patient compliance. Aims: To investigate the efficacy and safety of chidamide, tislelizumab, and pegaspargase in combination with radiotherapy as first-line treatment in high-risk stage I/II ENKTL. Methods: Patients with untreated, pathologically confirmed ENKTL, classified as stage I with at least one high-risk factor or stage II according to the Ann Arbor staging system, were enrolled. After they received four cycles of induction treatment, the patients who were evaluated as partial response (PR) or CR underwent sequential radiotherapy, followed by two additional cycles of induction therapy. The induction therapy regimen was as follows: chidamide, 20 mg PO, BIW; tislelizumab, 200 mg iv, D1; and pegaspargase, 2,000 U/m2 im, D1; 21 days/cycle. Intensity-modulated radiation therapy (IMRT) was used for radiotherapy. The primary study endpoints were the complete response rate (CRR) and objective response rate (ORR) after completing six cycles of induction therapy. The secondary study endpoints were progression-free survival (PFS), overall survival (OS), and safety. Results: Between March 2020 and March 2022, 37 patients were enrolled, whose median age was 51 (age range 20-72). Patients at stage I with high-risk factors accounted for 54.1% (20/37), and patients at stage II accounted for 45.9% (17/37). A total of 18 patients had a PINK-E score of 1 (48.6%), and the others had a score of 0 (51.4%) (Table 1). Efficacy evaluations were available for 28 patients (75.7%). The dose of chidamide was adjusted from 20 mg BIW to 5 mg PO QD in two cases because of digestive tract reactions, and in 14 cases, the initial usage of chidamide was adjusted to 5 mg QD in the whole process. The other patients followed the originally designed plan. There were 28 patients who obtained at least one therapeutic efficacy evaluation before radiation, whose ORR was 89.3% (25/28) and CRR was 71.4% (20/28). For the 24 patients who eventually completed the treatment regimen of CTP and radiotherapy, CRR and ORR were both 100%. For the 28 patients evaluable for efficacy, the median follow-up time was 36.5 months, and the median PFS and OS were both not reached. The 3-year PFS rate was estimated to be 81.2%, and the 3-year OS rate was 88.6%. The grade 3/4 hematologic AEs with incidence >5% were neutropenia (3/37, 8.1%), anemia (2/37, 5.4%), and thrombocytopenia (2/37, 5.4%). The grade 3/4 non-hematologic AEs were elevated ALT/AST (6/37, 16.2%) and upper gastrointestinal hemorrhage (2/37, 5.4%) (Table 2). There were five patients (13.5%) who terminated treatment or changed regimen because of AEs. The incidence rate of immune-related AEs was 40.5% (15/37), among which the incidence rate of grade 3 immune-related AEs was 8.1%. Conclusion: The CTP regimen in combination with radiotherapy as first-line treatment preliminarily indicated effectiveness for ENKTL at high-risk stages I and II. The patients had high CRR, PFS rate, OS rate and controllable adverse reactions. (NCT04414969)

Background Mantle cell lymphoma (MCL) is an uncommon lymphoproliferative disorder with extremely heterogeneous in both biological and clinical aspects. Its diverse clinical presentations necessitate a personalized prognostic model to stratify patients into subgroups with distinct survival outcomes. Methods Recognizing the limitations of existing models in capturing disease complexity, we utilized clinical and molecular data from nine Chinese medical centers to validate the progression of disease within 24 months (POD24) and to develop a novel prognostic risk model to predict the survival outcome of MCL patients. Results POD24 was observed in 37.7% of evaluable patients (369/979), with a significantly shorter median overall survival of 21 months compared to 122 months for those without POD24 (P < 0.0001).Patients with POD24 were more likely to present with B symptoms (P = 0.003), elevated lactate dehydrogenase (LDH) levels (P < 0.0001), splenomegaly (P < 0.0001), Ki-67 expression (P < 0.0001), and a poorer performance status (P = 0.005). Additionally, they were more likely to have undergone autologous stem cell transplantation (ASCT) (P = 0.037). The POD24-based risk model （POD24 ,age, LDH level, MIPI score, splenomegaly, Ki67 expression and ASCT）demonstrated the highest sensitivity for predicting survival, with an impressive area under the curve (AUC) for the risk score of 0.869. Conclusion Our study confirms the robust predictive power of POD24 and introduces a novel risk model that integrates POD24 with clinical factors. Our new prognostic model might be helpful to effectively classify MCL patients with high-risk groups in terms of survival rate, which may help select high-risk MCL patients for more intensive treatment at time of relapse. This novel developed model greatly improved the prognostic predictive accuracy, which could be used to individualize the survival outcomes of patients and has the potential translation into clinical practice in the future.

Background T/NK cell lymphomas (TNKCL) are aggressive malignancies with high rates of treatment failure and recurrence. Despite therapeutic advancements, including immune checkpoint inhibitors, antibody-drug conjugates (ADCs), and targeted drugs, their efficacy is limited. The tumor microenvironment (TME), particularly tumor-associated macrophages (TAMs), plays a crucial role in tumor progression and treatment response. TAMs, being highly plastic, offer a promising therapeutic target. Histone deacetylase inhibitors (HDACi) have shown efficacy against TNKCL, with five models approved. Chidamide, an HDACi targeting HDAC1/2/3/10, approved in China for relapsed or refractory peripheral T-cell lymphoma (PTCL), has shown an overall response rate of 28% and a median survival time of 21.4 months in relapsed or refractory PTCL, indicating a need to explore its mechanisms further. In this study, we investigated the effect of Chidamide on the phenotype of TAMs and its molecular mechanism, revealing the unique antitumor properties of Chidamide and expanding its clinical utility. Methods Macrophages from human and mouse sources were treated with varying Chidamide concentrations, and polarization was assessed by flow cytometry. A co-culture model evaluated macrophage phagocytic function in the presence of tumor cells. Inflammation-related gene and protein expressions were quantified using qPCR and Western blot. Reactive oxygen species (ROS) and metabolic indicators were measured with specific fluorescent probes. Biotinylated Chidamide was used in pull-down experiments to identify targets via mass spectrometry. Transcriptome sequencing and bioinformatics were utilized to identify variable splicing forms, confirmed by RT-PCR. T-cell lymphoma animal models were employed to test Chidamide's anti-tumor immunity and its synergistic effects with immune checkpoint inhibitors. Results Post-Chidamide treatment, a significant increase in M1 macrophages was observed in TNKCL patient peripheral blood mononuclear cells (PBDMs). Similar results were observed in healthy volunteer PBDMs. THP1 cells, and mouse bone marrow-derived macrophages, indicating Chidamide promotes M1 polarization. Co-culture models demonstrated enhanced macrophage phagocytosis. RNA sequencing (RNA-seq) of Chidamide-treated THP1 cells indicated activation of inflammatory pathways, indicative of a pro-inflammatory phenotype. In vivo, mice treated with Chidamide exhibited significant suppression of tumor growth, along with an increase in M1 macrophage infiltration, while the levels of CD8+ T cells and NK cells remained unchanged, indicating that the anti-lymphoma effect of Chidamide is macrophage-dependent. Comparative analysis with other HDACi showed Chidamide uniquely reprogram TAMs to M1, independent of HDAC targets. There were no significant differences in reactive oxygen species (ROS), lactate metabolism, and TAM-receptor tyrosine kinase (TAM-RTK) pathways, suggesting the involvement of a novel mechanism. The RNA splicing factor SF1 was identified as a target of Chidamide through biotin pull-down assays and mass spectrometry.SF1 knockdown abolished Chidamide's M1 polarization effect. RNA-seq showed significant reductions in exon skipping events in Chidamide-treated THP1 cells, with SETD4-L and PPWD1-L splicing variants promoting M1 polarization and stronger phagocytosis. The combination of Chidamide and anti-PD-1 antibody in mouse models showed enhanced tumor inhibition and M1 macrophage infiltration, indicating that the efficacy of immunotherapy is improved through M1 macrophage reprogramming. Conclusion Chidamide significantly enhances anti-lymphoma efficacy by promoting M1 macrophage polarization through a novel mechanism involving the splicing factor SF1 and specific splicing products, SETD4-L and PPWD1-L. The unique mechanism underlies Chidamide's superior clinical outcomes and its potential to enhance immunotherapy by modulating the TME.