Myelosuppression is a common and severe side effect of cancer chemotherapy, with current treatments hindered by limitations such as depletion of hematopoietic reserves, poor patient compliance, delayed therapeutic onset, and high cost. To overcome these challenges, we developed Epimedium-derived nanovesicles (ENVs) from the traditional Chinese medicinal herb Epimedium, addressing the solubility and bioavailability issues associated with conventional extracts. ENVs encapsulate bioactive constituents, including icariin and hematopoiesis-promoting ceramides. In a cyclophosphamide (CTX)-induced myelosuppression mouse model, prophylactic and therapeutic oral administration of ENVs effectively alleviated hematopoietic suppression, significantly outperforming the Epimedium-based herbal extract "Joungal" (Shengbai Formula) despite equivalent icariin content. Notably, ENVs promoted hematopoietic stem cell (HSC) proliferation-an outcome rarely achieved with existing therapies. Mechanistically, ENVs modulated the gut microbiota, enriching lactobacillus species and enhancing lactate production. This microbiota-driven lactate signaling stimulated LepR+mesenchymal stem cells (MSCs) in the bone marrow niche to secrete stromal cell-derived factor-1 (SDF-1) and stem cell factor (SCF), thereby supporting HSC expansion and restoring hematopoietic function. In vivo safety evaluations confirmed the excellent biocompatibility of ENVs. Our findings uncover a gut-lactate-bone marrow axis through which ENVs enhance hematopoiesis and promote HSC regeneration. This work introduces a cost-effective, scalable, and orally administrable biomaterial platform with strong translational potential for the prevention and treatment of chemotherapy-induced myelosuppression.

Multiple myeloma (MM) is an incurable malignancy exhibiting immune evasion and resistance to proteasome inhibitors like bortezomib. We engineered an oncolytic vaccinia virus encoding an anti-mouse CD47 nanobody (OVV-αCD47nb) that combines direct oncolysis with localized CD47-SIRPα axis blockade. OVV-αCD47nb maintained infectivity and secreted anti-CD47 nanobodies that enhanced macrophage phagocytosis of tumor cells. In murine MM models, OVV-αCD47nb suppressed tumor growth, extended survival, and induced durable responses without hematologic toxicity. Mechanistically, OVV-αCD47nb remodeled the tumor microenvironment by polarizing macrophages to M1-like phenotypes and enhancing CD8+ T cell infiltration and function. Transcriptomics revealed enriched pro-inflammatory and phagocytic pathways with downregulated autophagy genes. OVV-αCD47nb synergized with bortezomib to overcome resistance and improve tumor control over monotherapies. This multifunctional viro-immunotherapy strategy, which integrates oncolysis, immune reprogramming, and chemosensitization, offers a promising therapeutic approach for CD47-expressing malignancies.

OBJECTIVES:To clarify the antipyretic efficacy of Capilliposide (LC) and investigate its antipyretic mechanism. METHODS:Dry yeast was used to establish rats fever model. Five hours after inoculation, 60 and 80 mg/kg LC was given to rats (i.g.). Rectal temperatures were measured at 2.5 h after administration. Then, the rats were sacrificed and blood and brain tissues were collected. The levels of cytokines tumor necrosis factor-α , interleukin (IL)-1β, and IL-6 were determined in serum, and prostaglandin E2 expression was measured in the hypothalamic suspension. Additionally, nitric oxide (NO) production and pyrogenic cytokines were detected in the supernatant of RAW 264.7 cells with or without LC treatment. Transcriptional analysis was performed and verified using western blot analysis. KEY FINDINGS:LC treatment significantly decreased the rectal temperature compared to that in the fever model at 5 h. The levels of pyrogenic cytokines were reduced following LC treatment. LC alleviated the pathological damage of hypothalamus caused by fever. LC treatment also significantly reduced NO production in vitro. Western blot results showed that LC inhibited the nuclear factor kappa-B and mitogen-activated protein kinase (MAPK) signaling pathways. CONCLUSIONS:In summary, our results demonstrated that LC exhibited excellent anti-inflammatory and anti-pyretic effects in vivo and in vitro through MAPK/inducible nitric oxide synthase/NF-κB pathway.

Cancer immunotherapy currently represents the only promising strategy with the potential to achieve a complete cure for tumors. Enhancing tumor-specific immune responses and overcoming the immunosuppressive TME are key to improving the efficacy of cancer immunotherapy. In this study, we introduce a calcium carbonate-based nanocarrier capable of modulating the tumor microenvironment. This system is coloaded with L-arginine (L-Arg) and the chemotherapeutic agent doxorubicin (DOX), aiming to optimize the conventional chemoimmunotherapy approach by ameliorating the immunosuppressive tumor microenvironment and regulating immune cell activity, thereby promoting synergistic chemoimmunotherapeutic outcomes. Specifically, DOX directly kills tumor cells and induces immunogenic cell death. Moreover, the calcium carbonate nanocarrier not only serves as a drug delivery vehicle but also neutralizes lactic acid in the tumor tissue, thereby alleviating the acidic immunosuppressive microenvironment. Furthermore, it supplies supplemental arginine within the tumor tissue to increase the activation of effector T cells. Ultimately, this strategy achieves highly efficient antitumor efficacy through the combined and synergistic actions of chemotherapy and immunotherapy.

This Phase I/II clinical trial (NCT04471064) evaluated the preliminary efficacy, safety, and pharmacokinetics of XY0206, a novel oral FMS-like tyrosine kinase 3 (FLT3) inhibitor, in patients with relapsed or refractory acute myeloid leukemia (R/R AML). From September 2020 to December 2022, this open-label, multicenter study enrolled patients aged ≥ 18 years with R/R AML. The trial included dose-escalation and dose-expansion phases, with six cohorts receiving XY0206 at doses ranging from 12.5 to 62.5 mg once daily or 25 mg twice daily. Of the 61 enrolled participants, 37 had FLT3 mutation-positive (FLT3mut+) AML. The overall response rate (ORR) was 34.4% in the entire cohort and 48.6% in FLT3mut+ patients. Among FLT3mut+ patients, the composite complete remission rate (CRc) was 45.9%, including a complete remission (CR) rate of 5.4% and a CR with partial hematologic recovery (CRh) rate of 13.5% and a CR with incomplete hematologic recovery (CRi) rate of 27.0%. In patients with FLT3 internal tandem duplication (FLT3-ITD) mutations, the ORR was 56.7%, with a CRc of 53.3% (CR: 6.7%; CRh: 16.7% ; CRi: 30.0%). The 37.5 mg dose cohort, identified as the target dose, was expanded exclusively for FLT3mut+ patients. XY0206 exhibited a favorable safety profile and demonstrated potent antileukemic activity, particularly in FLT3mut+ R/R AML patients, supporting its further clinical development. Trial Registration: CTR20201214 (CDE); ClinicalTrials.gov ID: NCT04471064.

Therapeutic antibodies are widely used in cancer biotherapy due to their target specificity, mediating tumor cell inhibition, angiogenesis suppression, and immune modulation. However, systemic administration often leads to off-target effects, as many antibody targets are also expressed in normal tissues, limiting intratumoral drug concentration and causing adverse events. Oncolytic viruses (OVs), which selectively infect and lyse tumor cells while activating host anti-tumor immunity, offer a promising platform for localized antibody delivery. Their inherent tumor tropism, intratumoral administration, and high genetic manipulability enable the engineering of OVs to express exogenous antibodies within the tumor microenvironment, enhancing therapeutic specificity and synergizing oncolytic and immune-mediated effects. In this review, we summarize the biological properties of OVs, strategies for engineering antibody payloads, the mechanistic interplay between OV-induced oncolysis and immune modulation, and current challenges and opportunities for clinical translation. By integrating these aspects, we provide insights into optimizing OV-based antibody therapies for enhanced tumor-targeted efficacy and reduced systemic toxicity.

The thioredoxin (Trx) system, an integral component of cellular redox regulation, preserves protein dithiol-disulfide equilibrium through its conserved Cys-Gly-Pro-Cys active site and is involved in key cellular functions, including cell proliferation, apoptosis, and signal transduction. In cancer biology, the thioredoxin system plays dual roles: overexpression can suppress oxidative stress and promote tumor growth, whereas dysfunction can trigger programmed cell death (PCD). However, a critical area for future research is to delineate how Trx modulates the intricate networks of PCD, and to identify key nodes within these pathways that can be targeted for oncological therapy. This review outlines the structure and function of the thioredoxin system, highlighting its role in redox balance and its regulatory dynamics in healthy and disease states. We further examine the dual role of Trx by detailing its cross-regulatory networks that modulate diverse PCD pathways, including disulfidptosis, ferroptosis, apoptosis, autophagy, pyroptosis and necroptosis. In addition, we comprehensively outline therapeutic approaches that manipulate the Trx pathway to regulate PCD across a spectrum of health disorders, including malignancies, infectious diseases, neurodegenerative conditions, cardiovascular ailments, and metabolic dysfunctions. Finally, we address the current clinical applications of targeting the thioredoxin system. Although challenges such as tumor heterogeneity and drug-delivery efficiency persist, it remains a promising therapeutic avenue. This review aims to develop a theoretical framework and provide tactical guidance for the development of novel treatments targeting the Trx-PCD pathway.

Tumor necrosis factor (TNF) exerts paradoxical effects in cancer, driven by the differential engagement of its two receptors, TNFR1 and TNFR2. While TNFR1 mediates cytotoxic signaling, accumulating evidence indicates that TNFR2 predominantly orchestrates tumor-promoting inflammation and immunosuppression within the tumor microenvironment (TME). TNFR2 is highly expressed on regulatory T cells (Tregs), myeloid-derived suppressor cells (MDSCs), cancer-associated fibroblasts (CAFs), and malignant cells, forming a coordinated network that drives immune evasion and contributes to resistance to immune checkpoint blockade (ICB). In this review, we dissect the structural and functional distinctions between transmembrane and soluble TNF and discuss how these differences shape receptor-specific signaling outcomes. We further highlight emerging therapeutic strategies targeting the TNF–TNFR2 axis, including monoclonal antibodies, antibody–drug conjugates (ADCs), and bispecific antibodies, with an emphasis on their ability to selectively remodel the immunosuppressive TME. Finally, we discuss key challenges for clinical translation, including on-target toxicity, patient stratification, and context-dependent TNFR2 biology, and outline future directions such as biomarker-guided therapy and tumor-restricted targeting approaches. Together, these advances position TNFR2 as a promising therapeutic node for overcoming resistance to current immunotherapies.

The therapeutic landscape of hematologic malignancies has been transformed over the past decade by the shift from conventional chemotherapy to targeted therapies, including proteasome, tyrosine kinase, and epigenetic regulators. Although these agents have significantly improved patient survival outcomes, this progress is tempered by the emergence of distinct cardiovascular toxicities that threaten both patient quality of life and long-term prognosis. Current clinical management is limited by the lack of standardized adverse event reporting mechanisms in trials and the operational complexity of existing risk stratification tools. In this context, a streamlined, personalized surveillance strategy is warranted. Comprehensive baseline cardiovascular assessment is paramount, with the frequency and modality of subsequent monitoring tailored specifically to the agent’s mechanism of action and the patient’s underlying risk profile. Crucially, when cardiotoxicity arises, the utilization of multidisciplinary cardio-oncology teams is indicated to manage the cardiac condition therapeutically, thereby avoiding the premature discontinuation of life-saving oncologic therapy. The ultimate goal remains maximizing the potent antitumor efficacy of these targeted therapies while rigorously protecting cardiovascular function.

Lymphoma is a heterogeneous hematological malignancy with limited effective therapies. Oncolytic vaccinia virus (OVV) is a promising immunotherapy, but its monotherapeutic efficacy is suboptimal, showing weak antitumor activity in murine lymphoma models and inducing an immunosuppressive tumor microenvironment (TME) with more M2 macrophages and Tregs. This study aimed to improve OVV’s efficacy and translational feasibility by reversing the immunosuppressive TME and enhancing OVV-mediated antitumor immunity. We first explored IL-18’s effect on OVV-induced immunosuppressive TME, then engineered a recombinant OVV-hIL18 encoding human IL-18. We assessed its in vitro oncolytic activity, in vivo antitumor effect and safety in murine/humanized lymphoma models, and its TME-regulating mechanisms. IL-18 reversed OVV-induced immunosuppression by promoting M1 polarization and reducing Tregs, boosting OVV-mediated immunity. OVV-hIL18 had enhanced in vitro oncolysis, significantly inhibited tumor growth, prolonged survival in animal models without overt toxicity, and increased CD4⁺/CD8⁺ T cell infiltration, effector cytokine production and relieved T cell exhaustion in TME. IL-18-armed OVV overcomes OVV monotherapy limitations and enhances antitumor efficacy, providing theoretical and experimental support for its development as a next-generation immunotherapy for lymphoma.

Metabolic dysfunction-associated steatohepatitis (MASH) has become a global epidemic, and effective therapeutic strategies are urgently needed. Lonidamine (LND) has been reported to possess anti-inflammatory effects; however, few studies have investigated whether LND exerts a therapeutic effect on MASH. Therefore, in this study, we aim to explore the effects of LND on inflammatory responses and abnormal lipid metabolism in MASH mice. A mouse MASH model is established by feeding C57BL/6 mice a high-fat, high-cholesterol (CL) diet. The results show that LND attenuates CL-induced increases in body weight, serum glucose and lipid levels, inflammatory responses, and hepatocellular steatosis. In addition, the mitogen-activated protein kinase (MAPK) signaling pathway is inhibited, and the expression level of sterol regulatory element-binding protein 1 (SREBP1) protein is significantly reduced. Meanwhile, in vitro models of cellular inflammation and lipid metabolism are simulated, and molecular docking and biolayer interferometry (BLI) analysis are used to verify that LND and SREBP1 have a direct interaction and that LND promotes the degradation of SREBP1. Furthermore, specific knockdown of Srebp1 in AML12 cells is performed to further verify the effect of LND on MASH. The results confirm that LND exerts anti-inflammatory effects in MASH by inhibiting the activity of the MAPK signaling pathway and improves abnormal lipid metabolism through its interaction with SREBP1. Overall, LND holds promise as a potential therapeutic agent for the treatment of MASH.

Proteolysis-targeting chimeras (PROTACs) represent a revolutionary therapeutic strategy that achieves selective protein degradation through the ubiquitin-proteasome system, offering transformative potential for modulating programmed cell death (PCD) pathways. This review comprehensively examines the central role of PROTACs in regulating critical PCD mechanisms, including ferroptosis induction via GPX4 degradation, pyroptosis regulation through stimulator of interferon genes (STING) targeting, necroptosis modulation by MLKL/RIPK1 degradation, apoptosis activation through BCL-2/MDM2 elimination, and autophagy regulation via dual ubiquitin-proteasome and lysosomal pathways. These approaches effectively address the limitations of traditionally "undruggable" targets while demonstrating unique mechanistic properties and clinical promise. Currently, over 30 PROTAC candidates have entered clinical trials, including the estrogen receptor (ER) degrader ARV-471 for breast cancer and the IRAK4 degrader KT-474 for inflammatory diseases, both showing remarkable efficacy in overcoming drug resistance. While challenges remain in delivery systems, E3 ligase selectivity, and toxicity management, innovative technologies, such as nanocarriers, covalent PROTACs, and novel E3 ligases (e.g., RNF114) are advancing PROTAC applications in oncology, neurodegenerative disorders, and immune-related diseases. Future research will focus on optimizing molecular design, expanding the E3 ligase repertoire, and developing combination therapies. These efforts will establish PROTACs as groundbreaking solutions for intractable diseases, with their precise control of PCD pathways opening new therapeutic avenues. The technology's ability to selectively modulate cell death mechanisms positions it as a transformative approach in precision medicine.

Miscarriage is a prevalent early pregnancy complication, usually preceded by sub-optimal maternal serum human chorionic gonadotropin (hCG) growth. Normal trajectory of hCG doubling generally indicates a good start. However, we found that a group of patients who had developed early miscarriages despite having a normal hCG trajectory. We aimed to explore their causes underlying the peculiar phenomenon. The cohort included 60 cases out of 2975 patients with normal hCG growth during the study period (60/2975, 2.0%) that ended up with pregnancy loss. Their basic demographic data were compared, and the maternal age and BMI were similar across the groups. Their hCG growth patterns were also generally the same. By contrast, Group One had the least maternal medical or reproductive disorders but the most numbers of previous miscarriages. Regarding the gestational weeks of miscarriage, the results of the three groups were 9.0 [IQR: 8.0–9.0] wks, 8.0 [IQR: 7.0–8.0] wks, 8.0 [IQR: 7.0–9.0] wks, respectively. The survival of Group One is significantly longer when compared to Group Two and Group Three (P = 0.02), but most cases end up by ten weeks.Women with optimal hCG growth in early pregnancy are unlikely to end up with pregnancy loss, particularly after the first trimester. In contrast, women carrying aneuploid embryos may survive longer than anti-phospholipids antibodies positive patients. Most miscarriage cases presenting optimal β-hCG trajectory would stop growing by ten weeks.

Background:Radiographically confirmed pneumonia within 90 days of chemotherapy initiation is a frequent and clinically important complication in patients with non-Hodgkin lymphoma, yet interpretable tools for early individualized risk estimation are limited. Objective:To develop and internally validate an interpretable machine-learning model that predicts the 90-day risk of radiographically confirmed pneumonia after chemotherapy initiation in non-Hodgkin lymphoma. Methods:We retrospectively analyzed 205 chemotherapy-treated NHL patients. A two-step feature selection (LASSO followed by random-forest-based recursive feature elimination) identified four predictors: high-grade malignancy, drinking (alcohol use), estimated glomerular filtration rate (eGFR), and smoking. Five algorithms were trained and compared under a stratified 70/30 split (training n = 145; internal hold-out test set n = 60) with leakage-safe preprocessing (within-fold kNN imputation, SMOTE, and scaling). The gradient boosting machine (GBM) performed best and was interpreted using SHAP. A web-based prototype was implemented for research use only. Results:On the internal hold-out test set (n = 60), the GBM achieved an AUC of 0.855 (95% CI 0.746-0.964), an F1 score of 0.679, and a Brier score of 0.155. SHAP identified reduced eGFR, smoking, drinking, and high-grade malignancy as influential contributors; case-level waterfall and force plots enhanced transparency. These estimates reflect internal validation only and were obtained without systematic microbiological confirmation or standardized radiologic rescoring. Accordingly, performance may be optimistic, and real-world use is not advised pending temporal and multicenter external validation (with potential recalibration) and prospective evaluation. Conclusion:The interpretable GBM model demonstrated promising discrimination and calibration on an internal hold-out test set; however, clinical deployment requires temporal and multicenter external validation (as well as prospective assessment with potential recalibration). The accompanying web calculator is a research-only prototype and is not intended for clinical decision-making until such validation is completed.

Ferredoxins (FDXs) are evolutionarily conserved iron-sulfur (Fe-S) proteins that serve as master regulators of mitochondrial redox homeostasis, governing critical processes including electron transfer, energy metabolism, Fe-S cluster biogenesis, and steroidogenesis. In humans, the mitochondrial isoforms FDX1 and FDX2 exhibit specialized yet complementary functions: FDX1 directs steroidogenesis, protein lipoylation, and copper redox cycling, while FDX2 is a core factor in Fe-S cluster assembly. Crucially, dysregulation of these proteins disrupts mitochondrial integrity, impairs redox balance, and activates multiple programmed cell death (PCD) pathways such as cuproptosis, ferroptosis, apoptosis, and autophagic cell death. This review systematically analyzes their isoform-specific roles in mitochondrial electron transport, Fe-S cluster dynamics, metabolic regulation, and summarizes major advances in understanding how FDX1 and FDX2 orchestrate mitochondrial-PCD crosstalk. The work further examines their critical functions in PCD execution, including FDX1-mediated cuproptosis through Cu+-dependent aggregation of lipoylated proteins and FDX2-deficiency-driven ferroptosis via Fe-S cluster collapse and iron overload. Disease mechanisms across multiple pathologies, including cancer, neurodegeneration, cardiovascular disease, endocrine disorders, and genetic syndromes, are explored, highlighting links to FDX dysfunction, with emerging therapeutic strategies targeting FDXs also addressed. By elucidating the synergistic roles of FDX1 and FDX2 as metabolic-death gatekeepers, this review establishes a foundation for developing isoform-targeted therapies against diverse pathologies.

BACKGROUND:Drug-induced liver injury (DILI) is a leading cause of liver damage. It is especially prevalent in haematologic malignancies, complicating treatment regimens and posing a risk for severe outcomes such as acute liver failure. Antibody-based therapies have significantly improved treatment outcomes. However, these therapies are increasingly associated with liver injury, posing challenges in clinical management. AIMS:This review aims to examine the DILI associated with antibody-based therapies in haematologic malignancies, highlighting key mechanisms, risk factors, clinical management strategies, and identifying areas that require further research. METHODS:We conducted a comprehensive review of the literature on DILI induced by antibody-based therapies, including monoclonal antibodies, antibody-drug conjugates, and T-cell redirecting antibodies, specifically in the context of haematologic malignancies. RESULTS:DILI associated with antibody-based therapies varies from mild transaminase elevations to severe liver injury. Risk factors include pre-existing liver disease, genetic predisposition, and therapy-specific mechanisms such as immune-mediated liver damage or direct hepatotoxic effects. Current management strategies involve routine liver function monitoring, dose modifications, and therapy discontinuation in severe cases. However, standardised guidelines remain lacking. CONCLUSIONS:DILI remains a major challenge in the use of antibody-based therapies for haematologic malignancies. While progress has been made in understanding risk factors and management strategies, further research is essential to optimise patient care and balance therapeutic efficacy with liver toxicity risks.

BACKGROUND:Ubiquitin-specific peptidase 40(USP40), a member of the deubiquitinase family, regulates numerous cellular processes. Recent studies have increasingly highlighted the involvement of USP40 in cancer development. However, the precise mechanism through which USP40 influences acute myeloid leukemia (AML) progression remains poorly understood. METHODS:The expression levels of USP40 in AML tissues and cell lines were examined using Gene Expression Profiling Interactive Analysis, reverse transcription quantitative polymerase chain reaction (RT-qPCR), and western blotting (WB). The Kaplan-Meier plotter was used to evaluate the association between USP40 expression and prognosis in patients with AML. Cell Counting Kit-8, 5-ethynyl-2'-deoxyuridine incorporation, apoptosis assays, and subcutaneous tumor models in nude mice were applied to determine the effects of USP40 expression on AML cell proliferation and apoptosis in vitro and in vivo. WB, RT-qPCR, immunofluorescence assay, co-immunoprecipitation assay, and cycloheximide chase assay were conducted to explore the relationship between USP40 and c-MYC. Rescue experiments were further performed to assess the functional contribution of USP40-c-MYC axis to AML progression. RESULTS:USP40 was overexpressed in AML tissues and cell lines compared to normal controls and correlated with poor prognosis. USP40 accelerated AML progression by promoting proliferation and inhibiting apoptosis. Mechanistically, USP40 deubiquitinated c-MYC by selectively removing K48-linked polyubiquitin chains, thereby preventing its degradation via the ubiquitin-proteasome pathway. CONCLUSION:USP40 accelerated AML progression by deubiquitinating c-MYC, highlighting the USP40-c-MYC axis as a potential therapeutic target for AML treatment.

Abstract Background QLS32015 is a novel cis-link G-protein-coupled receptor class 5 member D (GPRC5D)×CD3 bispecific antibody, utilizing high-affinity GPRC5D and low-affinity CD3 arms to enhance T-cell-tumor bridging and reduce off-target T-cell activation. QLS32015 mediated potent cytotoxicity against cells expressing high or low level of GPRC5D. We previously reported initial safety and efficacy of QLS32015 in 13 RRMM pts (ASH 2024, Blood 2024;144 (Suppl 1):1990). Here, we present updated analyses in safety and efficacy from the dose-escalation/expansion phase Ⅰa/Ⅰb in 62 pts. Methods Eligible pts received QLS32015 (subcutaneously) in escalating weekly 2 step-up doses followed corresponding target doses for up to 2 years. Escalating doses (2/6/18 μg/kg QW and 54/100 μg/kg Q2W) were evaluated sequentially in phase Ⅰa. Three dose levels were selected for dose-expansion. The primary endpoints were the dose-limiting toxicity (DLT), maximum tolerated dose (MTD), recommend phase 2 dose (RP2D) and safety in phase Ia, and IMWG objective response rate (ORR) in phase Ib. Results As of Jun 20, 2025, 62 pts received QLS32015 (2–100 μg/kg). Median age was 61.0 years (range, 43–78), 54.8% of pts were diagnosed as IgG and 21.0% as light-chain subtypes. Among them, 40.3% had extramedullary disease (EMD), and 62.9% were revised-International Staging System stage II/III. Median lines of prior therapy was 3.0 (range, 1–8); 82.2% pts had ≥3 lines of therapy; 77.4% of pts were triple-class-exposed; 40.3% had one autologous stem cell transplant; and 25.8% had prior B-cell maturation antigen (BCMA)-targeted therapies. DLT occurred in only 1 pt at 54 μg/kg Q2W dose level. MTD was not reached. TRAEs of any grade (Gr) occurred in 58 (93.5%) pts. The most common TRAEs were hematological toxicities (88.7%) and cytokine release syndrome (CRS, 77.4%). The majority of CRS were Gr 1 (75.8%) or Gr 2 (12.9%), mainly in the first cycle, with a median onset time of 47.8 h (range, 4.4–603.8) and median duration of 2.0 days. No immune effector cell-associated neurotoxicity syndrome (ICANS) occurred. Mild to moderate skin and nail toxicity (predominantly Gr 1/2) was noticed, with skin-related TRAEs in 53.2% of pts and nail changes in 32.3%. Notably, only 1 pts experienced a Gr ≥3 skin-related TRAE. The most common infections were upper respiratory tract infections and pneumonia (Gr ≥3 19.4%). Within the study dose range, QLS32015 demonstrated dose-proportional increases in serum exposure from the first dose, with a PopPK-estimated half-life of 19.8 days. At doses of ≥54 μg/kg Q2W, the Ctrough exceeded the EC90 derived from efficacy tests in vitro. The dose-expansion to optimize dosing was conducted at dose levels of 36 g/kg Q2W, 54 g/kg Q2W, and 54 g/kg Q4W. RP2D was determined as 54 ug/kg Q2W integrated with safety data and PK parameters. Its long half-life supports Q4W or less frequent dosing strategies. As of cutoff date, median follow-up was 4.63 months (95% CI 3.42–6.05). Response was noticed from dose level of 6 μg/kg Q2W. In 52 efficacy-evaluable pts, ORR was 78.8% (95% CI 65.3–89.0). At RP2D (n=30), ORR was 86.7% (95% CI 69.3–96.2), with 70.0% ≥very good partial response (VGPR), 33.3% ≥complete response (CR), and 23.3% CR-minimal residual disease-negative. At RP2D, median time to response was 1.30 months (IQR, 0.92–1.51), and duration of response was not reached. Robust therapeutic efficacy was also observed in pts with poorer prognosis in the RP2D cohort, in particular, with ORR of 100% in pts with high-risk cytogenetics, 88.9% in pts with prior BCMA-targeted therapy, and 75.0% in pts with EMD. Median progression-free survival (PFS) at RP2D was not reached, with the 12-month PFS rate of 86.7% (95% CI 51.5–97.0). The median overall survival was not reached. In exposure-response analysis, RP2D derived better efficacy without increase in safety risk. Deep response rates (both ≥VGPR and ≥CR) escalated with cumulative exposure (all p<0.05), while no exposure-related increase in incidence of Gr ≥2 CRS, Gr ≥3 thrombocytopenia/neutropenia, or Gr ≥3/4 TRAEs (all p > 0.05). Conclusions QLS32015 showed manageable safety profile, with low incidence of GPRC5D-associated TRAEs and no occurrence of ICANS event. Notably, QLS32015 at RP2D exhibited remarkable preliminary efficacy in pts with high risk cytogenetics, prior BCMA-targeted therapy, or EMD. The long half-time of 19.8 days supports extended dosing intervals of QLS32015 with convenience and compliance.