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Background: While immunotherapy has transformed treatment paradigms for cancer, durable response rates remain below 30%. Currently available biomarkers are insufficient for precise patient stratification. Blood-based biomarkers, as minimally invasive and accessible tools, have attracted attention for their potential to dynamically monitor immune checkpoint inhibitor response.

Methods: Paired peripheral blood and tumor samples from 15 patients were analyzed using single-cell RNA sequencing and T cell receptor sequencing. To construct a comprehensive CD8⁺ T cell transcriptomic atlas, we integrated 13 publicly available single-cell datasets. A logistic regression-based model was trained on the transcriptional profiles of terminally differentiated effector memory CD8⁺ T (Temra) cells and then validated in a prospective, multi-center non-small cell lung cancer (NSCLC) cohort undergoing first-line immunotherapy.

Findings: Circulating Temra cells were the most clonally expanded CD8⁺ subset identified in peripheral blood. These cells exhibited distinct differentiation trajectories between responders and non-responders, with transcriptional profiles correlated with treatment efficacy. In the aggregated dataset comprising 748,082 CD8⁺ T cells, Temra transcriptional signatures were consistently associated with therapeutic outcomes. The predictive model, built upon the transcriptional profiles of Temra cells, achieved high accuracy (87%-95%) across two external validation cohorts. Validation in a prospective cohort of 131 patients with advanced NSCLC (ClinicalTrials.gov: NCT06054152) confirmed strong predictive performance (area under the curve [AUC] = 0.834).

Conclusions: Circulating Temra cells serve as robust predictors of immunotherapy efficacy. This study establishes a machine learning-based, pan-cancer, blood-derived transcriptomic biomarker that was prospectively validated in an NSCLC cohort and may substantially improve clinical decision-making in immuno-oncology.

Funding: This study was funded by the National Natural Science Foundation of China (no. 92259205).

Background: Chimeric antigen receptor (CAR) T cells targeting CD19 or B cell maturation antigen (BCMA) hold great promise to treat neuroimmune disorders, but the efficacy of CD19/BCMA dual-targeting CAR-T cells and their impact on systemic immunity are poorly understood.

Methods: In this phase 1 study (ClinicalTrials.gov: NCT06371040), patients with refractory generalized myasthenia gravis (gMG) received autologous CD19/BCMA CAR-T cells without prior lymphodepletion. The primary endpoint was the frequency and severity of treatment-emergent adverse events at week 4. Secondary endpoints included changes in MG-specific scale scores. Single-cell RNA sequencing and flow cytometry were performed to characterize longitudinal changes in B cell, plasma cell, and T cell compartments following CAR-T cell infusion.

Findings: CD19/BCMA CAR-T cells expanded in vivo, leading to depletion of B cells and plasma cells. All six patients had a favorable safety profile. Minimal symptom expression (MG Activities of Daily Living Score [MG-ADL] = 0) was achieved in five patients by day 90, with responses sustained through day 120-150, and all patients discontinued glucocorticoids while reducing immunosuppressant use. Immune profiling revealed a transient decline in memory B cells and plasma cells. The repopulated B cells exhibited attenuated B cell receptor signaling and increased inhibitory signals derived from bone marrow niche cells. Further, clonal expansion of T and B cells was significantly reduced.

Conclusions: CD19/BCMA CAR-T cell therapy is safe and effective in refractory gMG without lymphodepletion, leading to systemic immune reset that warrants future investigations in larger clinical trials.

Funding: This study was supported by the National Key Research and Development Program and the National Natural Science Foundation of China.

Background: Recurrent/metastatic (R/M) nasopharyngeal carcinoma (NPC) patients who failed platinum-based chemotherapy, with or without PD-1/L1 inhibitors, face limited treatment options. We evaluated the efficacy and safety of MRG003 (becotatug vedotin), an epidermal growth factor receptor (EGFR)-targeted antibody-drug conjugate (ADC), in previously treated R/M NPC.

Methods: This multicenter, single-arm, phase IIa study was part of a phase II trial (NCT05126719). Eligible patients received MRG003 (2.0 or 2.3 mg/kg) intravenously every 3 weeks. The primary endpoint was independent review committee (IRC)-assessed objective response rate (ORR); disease control rate (DCR), duration of response (DoR), progression-free survival (PFS), overall survival (OS), and safety were secondary endpoints.

Findings: Sixty-one patients were enrolled with a median follow-up of 21.9 months. IRC-assessed ORR and DCR were 42% (95% confidence interval [CI], 30-56) and 81% (95% CI, 69-90), respectively. Median DoR and PFS were 8.0 months (95% CI, 4.6-not evaluable [NE]) and 5.8 months (95% CI, 3.3-7.6), respectively. Median OS reached 15.8 months (95% CI, 11.0-NE) for all patients and 25.2 months (95% CI, 11.0-NE) for 2.3 mg/kg. Among 33 patients who had failed PD-1/L1 inhibitors and ≥2 prior chemotherapy lines, ORR and DCR were 30% and 76%, respectively. Grade ≥3 treatment-related adverse events occurred in 24 patients (39%). No treatment-related deaths occurred.

Conclusions: MRG003 demonstrated promising efficacy and manageable safety in pretreated R/M NPC patients. This is also the first long-term evaluation of an EGFR-targeted ADC in this population.

Funding: Study was supported by Shanghai Miracogen Inc, one subsidiary of Lepu Biopharma Co., Ltd.

Chimeric antigen receptor (CAR)-T cell therapy has transformed the treatment of hematological malignancies. However, its application in treating solid tumors has encountered significant obstacles. This review explores the current state of CAR-T cell therapy for solid tumors, highlighting challenges including the pronounced heterogeneity of tumor antigens and the immunosuppressive tumor microenvironment. We explore a range of preclinical and clinical strategies to enhance the efficacy of solid tumor CAR-T cells. These strategies encompass engineering chimeric receptors that can simultaneously target multiple antigens expressed by tumor cells, as well as implementing combination therapies and armored CAR-T cells to overcome existing limitations. While encouraging advancements using solid tumor CAR-T cell therapies have been seen, addressing intrinsic challenges remains a significant endeavor. Ongoing investigation of these innovative strategies is essential for the successful application of CAR-T cells in the context of solid tumors.

Despite advances in PET/CT, tissue confirmation remains essential for mediastinal lymphadenopathy. EBUS-TBNA is minimally invasive but limited by cytology, particularly in benign disease and lymphoma. Emerging EBUS-guided techniques, notably transbronchial mediastinal cryobiopsy, improve diagnostic yield where tissue architecture is required. The multicenter randomized study¹ strengthens evidence for its added value, while underscoring the need for selective application and standardized, indication-specific trials.

Placebo-controlled randomized controlled trials (RCTs) have long represented the sine qua non for determining treatment efficacy in inflammatory bowel disease (IBD). As the therapeutic armamentarium evolves and concerns regarding clinical equipoise intensify, there is increasing interest in comparative effectiveness research (CER). By harnessing real-world data, CER offers a powerful framework to inform treatment selection in an increasingly complex therapeutic environment.

Cell-free DNA (cfDNA) has emerged as a pivotal biomarker with significant implications across medical fields, including non-invasive prenatal testing and oncology. As cfDNA reflects the physiological and pathological states of the body, a detailed understanding of the biology of cfDNA, including the origins, production, circulation, and clearance, is crucial for advancing its diagnostic applications. This review offers a detailed account of the current understanding of the biology of cfDNA, integrating findings to explore mechanistic insights underlying the production and clearance of cfDNA. We discuss how this interplay is altered in various pathophysiological states-including cancer, pregnancy, systemic lupus erythematosus, infectious diseases, and transplantation-and highlight areas that warrant further characterization. Understanding these processes is essential in studying cfDNA dynamics in health and disease, providing novel insights that could expedite developments that further expand the utility of cfDNA-based diagnostic tests, and pave the way for more personalized applications of cfDNA.

Background: The characteristics of listeriosis in children beyond the neonatal period are unknown.

Methods: MONALISA is a prospective cohort study of listeriosis in France. All children aged 1 month to 18 years with microbiologically confirmed infection were enrolled.

Findings: We included 48 children among the 1,646 MONALISA patients (3%): 29/48 (60%) with neurolisteriosis, 12/48 (25%) with bacteremia, 6/48 (13%) with abdominal infection (gastroenteritis [n = 4] and appendicitis [n = 2]), and 1 with skin abscess. The median age was 4 years (interquartile range [IQR]: 25-75, range: 1-10), 23 were male (23/48, 48%), and 16 (16/48, 33%) reported at least one past medical event: 8/12 (67%) of those with bacteremia but only 8/29 (28%) of those with neurolisteriosis (p = 0.034) and none of the seven children with other forms. Diarrhea was reported in 21/48 children (44%) and was equally distributed among the different forms. Neurolisteriosis presented as meningoencephalitis (13/29, 45%) or isolated meningitis (16/29, 55%). Twenty-three children with neurolisteriosis presented without known immunosuppression (23/29, 79%), including 20 of the 22 children younger than 5 years (90%). Fourteen patients (14/48, 29%) required intensive care unit management. There were four in-hospital deaths (4/48, 8%), two attributed to listeriosis. All surviving children with neurolisteriosis recovered without permanent disability.

Conclusion: Listeriosis in children has specificities: neurolisteriosis in younger children most often occurs in the absence of immunosuppression and often presents as isolated meningitis, abdominal forms are more common than in adults, and the outcome is much better than in adults.

Funding: This work was funded by Institut Pasteur, INSERM, Santé Publique France, and Program Hospitalier de Recherche Clinique.

Coagulation factor XI (FXI) is an emerging target for venous and arterial thrombosis. While arterial prevention studies yield conflicting results, FXI(a) inhibition may be most effective as add-on therapy. Potential off-target cardiovascular effects, including blood pressure lowering and altered cardiac function, remain inconsistent. Ongoing trials should therefore assess both intended antithrombotic efficacy and unintended cardiovascular consequences.

Background: Chronic obstructive pulmonary disease (COPD) is a frequent comorbidity in non-small cell lung cancer (NSCLC) and has been clinically associated with improved responses to programmed cell death protein-1 (PD-1) blockade. Whether this enhancement is directly attributable to COPD and the mechanisms driving it remains unclear.

Methods: We conducted an integrated translational study combining three clinical cohorts with multi-omics profiling, including single-cell RNA sequencing, spatial transcriptomics, and multiplex immunofluorescence. Fresh surgical tumor specimens were subsequently used to perform in vitro functional assays to validate epithelial-immune interactions identified through multi-omics analyses.

Findings: COPD induces epithelial remodeling that expands a distinct basal-like tumor cell population with progenitor-like features in NSCLC. These cells activate a dominant CXCL14-CXCR4 signaling axis to preferentially recruit macrophages producing CXCL9, thereby establishing a localized microenvironment that is more permissive for cytotoxic T cell infiltration. This spatially restricted tumor-macrophage recruitment circuit was functionally validated and found to be enriched in patients with NSCLC who achieved a major pathological response following neoadjuvant anti-PD-1 therapy.

Conclusions: Our findings define a mechanistic link between COPD comorbidity and enhanced PD-1 blockade efficacy. The presence of this tumor-macrophage axis in patients with NSCLC with favorable immunotherapy outcomes highlights its translational potential as both a predictive biomarker and a therapeutic target to improve checkpoint blockade responsiveness.

Funding: This work was supported by the Noncommunicable Chronic Diseases-National Science and Technology Major Project (2024ZD0529403) and the National Natural Science Foundation of China (82370028, 82422001, 32330061, and 82303972).