Song et al. demonstrate that MHC-II-restricted neoantigen vaccine reverses the cold tumor microenvironment by promoting both CD4+ and CD8+ T cell infiltration and function. Its combination with TIGIT blockade showed enhanced anti-tumor efficacy by enhancing antigen-specific CD4+ T cell cytotoxicity and delaying T cell exhaustion.

Cohen et al. identify microRNA isoforms, known as isomiRs, as a new class of blood-based biomarkers in amyotrophic lateral sclerosis (ALS). Using machine learning and survival modeling across two large independent cohorts, they show that higher levels of isomiR-let-7g-5p.t robustly predict longer survival, with performance comparable to that of established clinical biomarkers.

Malki et al. provide a comprehensive review of the biology of circulating cell-free DNA (cfDNA) in blood. They explore the life cycle of cfDNA, including the biological mechanisms of cfDNA production, circulation, and clearance. The review also emphasizes cfDNA dynamics in various pathophysiological conditions, offering insights to enhance cfDNA-based diagnostic applications.

The rise of network-based approaches has advanced systems-level insights in medicine but presents challenges that must be addressed. This perspective identifies core limitations and recommends actionable steps to advance the field toward practical medical applications.

Nasopharyngeal carcinoma (NPC) is closely linked to EBV, but the predictive and protective roles of EBV-specific functional antibodies remain unclear. Roy et al. analyzed 353 individuals, finding broad FcγR activity in patients with NPC, early IgM and FcγR changes before disease, and antibody profiles associated with survival, highlighting their biomarker potential.

Like their mothers, infants born to mothers with IBD show gut microbiome alterations. Transplantation of these microbiomes to mice causes metabolomic and gene expression changes consistent with a reduced barrier function.

Cognitive impairment is a core feature of depression. Badulescu et al. tested the efficacy of oral semaglutide for the treatment of cognitive dysfunction in the first RCT conducted in patients with a mood disorder. They found that semaglutide was psychiatrically safe but not effective at improving executive function.

Cai et al. present a novel patient-level computer model simulating atrial fibrillation (AF) episodes, progression, and clinical outcomes across a lifetime, reproducing numerous real-world studies. Virtual randomized trials show improved AF detection from screening, while stroke prevention is modest and depends on individual risk profiles, timely treatment, and anticoagulation efficacy.

Kadhim et al. evaluated large language models (LLMs) to structure 32,041 inflammatory bowel disease histology and radiology reports into standardized, ontology-linked variables. Llama 3.3 achieved the highest performance, and fine-tuning a compact Llama 3.1 8B model improved imaging extraction with lower computational demand. These findings suggest that LLMs can enable scalable, privacy-preserving electronic health record structuring for research and future clinical decision support.

In the first prostate cancer trial of intratumoral immunotherapy, sequential intratumoral and intramuscular poly-ICLC was safe and well tolerated in patients with intermediate- to high-risk localized disease. Treatment induced local and systemic immune activation and remodeled the tumor microenvironment, supporting further evaluation of this in situ autovaccination strategy.

A tiered school-family-clinic intervention integrated with mobile health tools was deployed in Chinese primary schools and tailored to baseline weight. Over one school year, the program attenuated BMI gain, reduced obesity prevalence, and improved health behaviors, offering a scalable, low-cost model for broader public health adoption.

Zhang et al. report on the dose-escalation phase 1 trial of the BET inhibitor TQB3617 in patients with relapsed or refractory lymphomas. TQB3617 demonstrates an acceptable safety profile and promising antitumor activity, warranting further investigation in a phase 2 trial.

A multidisciplinary panel developed the first international expert consensus, including 30 evidence- and expertise-based statements on gene therapy for hereditary hearing loss using the modified Delphi method. The consensus standardizes clinical trial design and patient management, with immediate applicability to OTOF-related hearing loss and adaptability to other genetic forms.

The optimal surgical strategy for recurrent adult-type diffuse glioma is controversial. This study finds that ideal surgical goals depend on the tumor’s molecular type, providing an evidence-based framework to guide personalized treatment and predict patient outcomes.

This review traces the evolution of endovascular therapy for acute ischemic stroke, from pioneering trials to current standards of care. It discusses technical advances, patient selection, and future challenges, providing an integrated perspective on how endovascular therapy has transformed stroke treatment over the past two decades.

This review highlights recent advances in the management of acute ischemic stroke with a focus on intravenous thrombolysis. It synthesizes pivotal clinical trials and emerging concepts, outlining current evidence and future directions in the quest to improve outcomes after ischemic stroke.

Jia et al. analyze 1,005 randomized clinical trials and find that trials from low/middle-income countries report significantly larger treatment effects than those from high-income countries, especially for patient-reported outcomes. The discrepancies are smaller for trials with a low risk of bias, suggesting that bias might contribute to the discrepancies.

This first-in-human, dose-escalation trial demonstrates that intrarectal administration of perfluorodecalin is safe and well tolerated in healthy volunteers, with no systemic absorption. These findings provide the foundational safety data to advance enteral ventilation as a novel therapeutic strategy for patients with respiratory failure.

Targeted therapies have transformed the CLL treatment landscape, but resistance and intolerance are challenges. Here, Davids and colleagues report a phase 1b/2 clinical trial showing that, with a 5- to 7-day ramp-up, lisaftoclax (with or without rituximab or acalabrutinib) was well tolerated and showed promising activity in patients with CLL.

Geist et al. developed metabolic organ networks from whole-body FDG-PET scans to detect shifts in glucose metabolism between organs. Network density and disorder correlated with allostatic load as inferred from cancer, obesity, and inflammation, offering a robust systems-level correlate of metabolic health with the potential to detect erosion of health independent of specific disease-related changes.

By investigating the dynamics of gut microbiota (GMs) in patients with lung cancer receiving chemoradiotherapy with consolidation immunotherapy, Wu et al. demonstrate that Akkermansia abundance increases after chemoradiotherapy, serving as a promising prognostic biomarker. The results also present distinct GM profiles for patients with or without treatment-related pneumonia.

Mitochondrial genetics are increasingly recognized as a key contributor to Parkinson’s disease. This perspective highlights how long-read sequencing enables higher resolution of mitochondrial variation and underscores the importance of integrating nuclear and mitochondrial genome analysis to advance understanding of disease pathogenesis.

This trial compared photodynamic therapy versus placebo in 402 women with cervical high-grade squamous intraepithelial lesions. The 6-month response rate, as defined by normal histology or low-grade squamous intraepithelial lesion histology plus human papillomavirus clearance, was higher in the photodynamic therapy group (41.1% versus 21.7%, p < 0.001).

This study evaluates the efficacy and safety of TQB2450 plus IMRT in patients with rNPC and demonstrates that the combination exhibits promising antitumor activity with manageable toxicity. MIF expression, tumor microenvironment characteristics, TCR diversity, and serial plasma EBV DNA levels could identify patients who would benefit from this therapeutic strategy.