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Received — 23 October 2025 ⏭ Favourites

MSC-Bench: A Rigorous Benchmark for Multi-Server Tool Orchestration

✇cs.AI, q-bio.NC updates on arXiv.org
By: Jia-Kai Dong · I-Wei Huang · Chun-Tin Wu · Yi-Tien Tsai
23 October 2025 at 12:00
arXiv:2510.19423v1 Announce Type: new Abstract: We introduce MSC-Bench, a large-scale benchmark for evaluating multi-hop, end-to-end tool orchestration by LLM agents in a hierarchical Model-Context Protocol (MCP) ecosystem. Existing benchmarks often evaluate tools in isolation, ignoring challenges such as functional overlap and cross-server orchestration, leading to overly optimistic assessments. MSC-Bench addresses these gaps by constructing ground truth through 'equal function sets', allowing objective metrics such as F1 score and reducing the dependency on LLM-as-a-judge evaluation. Organized as a five-level curriculum, it systematically tests agent capabilities from single-tool orchestration to complex cross-server planning, and robustness to out-of-scope requests. Experiments reveal that rigid hierarchies can hinder performance without co-designed strategies, and even state-of-the-art agents exhibit systemic weaknesses in robustness. MSC-Bench provides a diagnostic framework to expose these limitations and guide the development of more capable and efficient tool-using agents. The benchmark and resources are publicly available at https://github.com/snooow1029/MSC_Bench.
  • ✇cs.AI, q-bio.NC updates on arXiv.org
  • Small Language Models Offer Significant Potential for Science Community Jian Zhang
    arXiv:2510.18890v1 Announce Type: cross Abstract: Recent advancements in natural language processing, particularly with large language models (LLMs), are transforming how scientists engage with the literature. While the adoption of LLMs is increasing, concerns remain regarding potential information biases and computational costs. Rather than LLMs, I developed a framework to evaluate the feasibility of precise, rapid, and cost-effective information retrieval from extensive geoscience literature
     
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Small Language Models Offer Significant Potential for Science Community

✇cs.AI, q-bio.NC updates on arXiv.org
By: Jian Zhang
23 October 2025 at 12:00
arXiv:2510.18890v1 Announce Type: cross Abstract: Recent advancements in natural language processing, particularly with large language models (LLMs), are transforming how scientists engage with the literature. While the adoption of LLMs is increasing, concerns remain regarding potential information biases and computational costs. Rather than LLMs, I developed a framework to evaluate the feasibility of precise, rapid, and cost-effective information retrieval from extensive geoscience literature using freely available small language models (MiniLMs). A curated corpus of approximately 77 million high-quality sentences, extracted from 95 leading peer-reviewed geoscience journals such as Geophysical Research Letters and Earth and Planetary Science Letters published during years 2000 to 2024, was constructed. MiniLMs enable a computationally efficient approach for extracting relevant domain-specific information from these corpora through semantic search techniques and sentence-level indexing. This approach, unlike LLMs such as ChatGPT-4 that often produces generalized responses, excels at identifying substantial amounts of expert-verified information with established, multi-disciplinary sources, especially for information with quantitative findings. Furthermore, by analyzing emotional tone via sentiment analysis and topical clusters through unsupervised clustering within sentences, MiniLM provides a powerful tool for tracking the evolution of conclusions, research priorities, advancements, and emerging questions within geoscience communities. Overall, MiniLM holds significant potential within the geoscience community for applications such as fact and image retrievals, trend analyses, contradiction analyses, and educational purposes.

"Over-the-Hood" AI Inclusivity Bugs and How 3 AI Product Teams Found and Fixed Them

✇cs.AI, q-bio.NC updates on arXiv.org
By: Andrew Anderson · Fatima A. Moussaoui · Jimena Noa Guevara · Md Montaser Hamid · Margaret Burnett
23 October 2025 at 12:00
arXiv:2510.19033v1 Announce Type: cross Abstract: While much research has shown the presence of AI's "under-the-hood" biases (e.g., algorithmic, training data, etc.), what about "over-the-hood" inclusivity biases: barriers in user-facing AI products that disproportionately exclude users with certain problem-solving approaches? Recent research has begun to report the existence of such biases -- but what do they look like, how prevalent are they, and how can developers find and fix them? To find out, we conducted a field study with 3 AI product teams, to investigate what kinds of AI inclusivity bugs exist uniquely in user-facing AI products, and whether/how AI product teams might harness an existing (non-AI-oriented) inclusive design method to find and fix them. The teams' work resulted in identifying 6 types of AI inclusivity bugs arising 83 times, fixes covering 47 of these bug instances, and a new variation of the GenderMag inclusive design method, GenderMag-for-AI, that is especially effective at detecting certain kinds of AI inclusivity bugs.

Interpretable Question Answering with Knowledge Graphs

✇cs.AI, q-bio.NC updates on arXiv.org
By: Kartikeya Aneja · Manasvi Srivastava · Subhayan Das · Nagender Aneja
23 October 2025 at 12:00
arXiv:2510.19181v1 Announce Type: cross Abstract: This paper presents a question answering system that operates exclusively on a knowledge graph retrieval without relying on retrieval augmented generation (RAG) with large language models (LLMs). Instead, a small paraphraser model is used to paraphrase the entity relationship edges retrieved from querying the knowledge graph. The proposed pipeline is divided into two main stages. The first stage involves pre-processing a document to generate sets of question-answer (QA) pairs. The second stage converts these QAs into a knowledge graph from which graph-based retrieval is performed using embeddings and fuzzy techniques. The graph is queried, re-ranked, and paraphrased to generate a final answer. This work includes an evaluation using LLM-as-a-judge on the CRAG benchmark, which resulted in accuracies of 71.9% and 54.4% using LLAMA-3.2 and GPT-3.5-Turbo, respectively.

KnowMol: Advancing Molecular Large Language Models with Multi-Level Chemical Knowledge

✇cs.AI, q-bio.NC updates on arXiv.org
By: Zaifei Yang · Hong Chang · Ruibing Hou · Shiguang Shan · Xilin Chen
23 October 2025 at 12:00
arXiv:2510.19484v1 Announce Type: cross Abstract: The molecular large language models have garnered widespread attention due to their promising potential on molecular applications. However, current molecular large language models face significant limitations in understanding molecules due to inadequate textual descriptions and suboptimal molecular representation strategies during pretraining. To address these challenges, we introduce KnowMol-100K, a large-scale dataset with 100K fine-grained molecular annotations across multiple levels, bridging the gap between molecules and textual descriptions. Additionally, we propose chemically-informative molecular representation, effectively addressing limitations in existing molecular representation strategies. Building upon these innovations, we develop KnowMol, a state-of-the-art multi-modal molecular large language model. Extensive experiments demonstrate that KnowMol achieves superior performance across molecular understanding and generation tasks. GitHub: https://github.com/yzf-code/KnowMol Huggingface: https://hf.co/datasets/yzf1102/KnowMol-100K

Insights into the Unknown: Federated Data Diversity Analysis on Molecular Data

✇cs.AI, q-bio.NC updates on arXiv.org
By: Markus Bujotzek · Evelyn Trautmann · Calum Hand · Ian Hales
23 October 2025 at 12:00
arXiv:2510.19535v1 Announce Type: cross Abstract: AI methods are increasingly shaping pharmaceutical drug discovery. However, their translation to industrial applications remains limited due to their reliance on public datasets, lacking scale and diversity of proprietary pharmaceutical data. Federated learning (FL) offers a promising approach to integrate private data into privacy-preserving, collaborative model training across data silos. This federated data access complicates important data-centric tasks such as estimating dataset diversity, performing informed data splits, and understanding the structure of the combined chemical space. To address this gap, we investigate how well federated clustering methods can disentangle and represent distributed molecular data. We benchmark three approaches, Federated kMeans (Fed-kMeans), Federated Principal Component Analysis combined with Fed-kMeans (Fed-PCA+Fed-kMeans), and Federated Locality-Sensitive Hashing (Fed-LSH), against their centralized counterparts on eight diverse molecular datasets. Our evaluation utilizes both, standard mathematical and a chemistry-informed evaluation metrics, SF-ICF, that we introduce in this work. The large-scale benchmarking combined with an in-depth explainability analysis shows the importance of incorporating domain knowledge through chemistry-informed metrics, and on-client explainability analyses for federated diversity analysis on molecular data.

A Goal-Driven Survey on Root Cause Analysis

✇cs.AI, q-bio.NC updates on arXiv.org
By: Aoyang Fang · Haowen Yang · Haoze Dong · Qisheng Lu · Junjielong Xu · Pinjia He
23 October 2025 at 12:00
arXiv:2510.19593v1 Announce Type: cross Abstract: Root Cause Analysis (RCA) is a crucial aspect of incident management in large-scale cloud services. While the term root cause analysis or RCA has been widely used, different studies formulate the task differently. This is because the term "RCA" implicitly covers tasks with distinct underlying goals. For instance, the goal of localizing a faulty service for rapid triage is fundamentally different from identifying a specific functional bug for a definitive fix. However, previous surveys have largely overlooked these goal-based distinctions, conventionally categorizing papers by input data types (e.g., metric-based vs. trace-based methods). This leads to the grouping of works with disparate objectives, thereby obscuring the true progress and gaps in the field. Meanwhile, the typical audience of an RCA survey is either laymen who want to know the goals and big picture of the task or RCA researchers who want to figure out past research under the same task formulation. Thus, an RCA survey that organizes the related papers according to their goals is in high demand. To this end, this paper presents a goal-driven framework that effectively categorizes and integrates 135 papers on RCA in the context of cloud incident management based on their diverse goals, spanning the period from 2014 to 2025. In addition to the goal-driven categorization, it discusses the ultimate goal of all RCA papers as an umbrella covering different RCA formulations. Moreover, the paper discusses open challenges and future directions in RCA.

Integrating Transparent Models, LLMs, and Practitioner-in-the-Loop: A Case of Nonprofit Program Evaluation

✇cs.AI, q-bio.NC updates on arXiv.org
By: Ji Ma · Albert Casella
23 October 2025 at 12:00
arXiv:2510.19799v1 Announce Type: cross Abstract: Public and nonprofit organizations often hesitate to adopt AI tools because most models are opaque even though standard approaches typically analyze aggregate patterns rather than offering actionable, case-level guidance. This study tests a practitioner-in-the-loop workflow that pairs transparent decision-tree models with large language models (LLMs) to improve predictive accuracy, interpretability, and the generation of practical insights. Using data from an ongoing college-success program, we build interpretable decision trees to surface key predictors. We then provide each tree's structure to an LLM, enabling it to reproduce case-level predictions grounded in the transparent models. Practitioners participate throughout feature engineering, model design, explanation review, and usability assessment, ensuring that field expertise informs the analysis at every stage. Results show that integrating transparent models, LLMs, and practitioner input yields accurate, trustworthy, and actionable case-level evaluations, offering a viable pathway for responsible AI adoption in the public and nonprofit sectors.

RoboGPT-R1: Enhancing Robot Planning with Reinforcement Learning

✇cs.AI, q-bio.NC updates on arXiv.org
By: Jinrui Liu · Bingyan Nie · Boyu Li · Yaran Chen · Yuze Wang · Shunsen He · Haoran Li
23 October 2025 at 12:00
arXiv:2510.14828v2 Announce Type: replace Abstract: Improving the reasoning capabilities of embodied agents is crucial for robots to complete complex human instructions in long-view manipulation tasks successfully. Despite the success of large language models and vision language models based on Supervised Fine-Tuning (SFT) in planning tasks, they continue facing challenges in performing long-horizon manipulation tasks in complex real-world environments, owing to their restricted common sense and reasoning capabilities. Considering that aligning general-purpose vision language models to robotic planning tasks via supervised fine-tuning suffers from poor generalization and insufficient physical understanding, we propose RoboGPT-R1, a two-stage fine-tuning framework for embodied planning. In this framework, supervised training acquires foundational knowledge through expert sequences, followed by RL to address the model's shortcomings in visual-spatial understanding and reasoning. To achieve physical understanding and action sequence consistency in multi-step reasoning tasks, we design a rule-based reward function that simultaneously considers long-horizon performance and action constraint in the environment. The reasoning model, trained on Qwen2.5-VL-3B, significantly outperforms the larger-scale model, GPT-4o-mini, by 21.33% and surpasses other work trained on Qwen2.5-VL-7B by 20.33% on the EmbodiedBench benchmark.

The Right to Be Remembered: Preserving Maximally Truthful Digital Memory in the Age of AI

✇cs.AI, q-bio.NC updates on arXiv.org
By: Alex Zhavoronkov · Dominika Wilczok · Roman Yampolskiy
23 October 2025 at 12:00
arXiv:2510.16206v2 Announce Type: replace Abstract: Since the rapid expansion of large language models (LLMs), people have begun to rely on them for information retrieval. While traditional search engines display ranked lists of sources shaped by search engine optimization (SEO), advertising, and personalization, LLMs typically provide a synthesized response that feels singular and authoritative. While both approaches carry risks of bias and omission, LLMs may amplify the effect by collapsing multiple perspectives into one answer, reducing users ability or inclination to compare alternatives. This concentrates power over information in a few LLM vendors whose systems effectively shape what is remembered and what is overlooked. As a result, certain narratives, individuals or groups, may be disproportionately suppressed, while others are disproportionately elevated. Over time, this creates a new threat: the gradual erasure of those with limited digital presence, and the amplification of those already prominent, reshaping collective memory. To address these concerns, this paper presents a concept of the Right To Be Remembered (RTBR) which encompasses minimizing the risk of AI-driven information omission, embracing the right of fair treatment, while ensuring that the generated content would be maximally truthful.

LICO: Large Language Models for In-Context Molecular Optimization

✇cs.AI, q-bio.NC updates on arXiv.org
By: Tung Nguyen · Aditya Grover
23 October 2025 at 12:00
arXiv:2406.18851v2 Announce Type: replace-cross Abstract: Optimizing black-box functions is a fundamental problem in science and engineering. To solve this problem, many approaches learn a surrogate function that estimates the underlying objective from limited historical evaluations. Large Language Models (LLMs), with their strong pattern-matching capabilities via pretraining on vast amounts of data, stand out as a potential candidate for surrogate modeling. However, directly prompting a pretrained language model to produce predictions is not feasible in many scientific domains due to the scarcity of domain-specific data in the pretraining corpora and the challenges of articulating complex problems in natural language. In this work, we introduce LICO, a general-purpose model that extends arbitrary base LLMs for black-box optimization, with a particular application to the molecular domain. To achieve this, we equip the language model with a separate embedding layer and prediction layer, and train the model to perform in-context predictions on a diverse set of functions defined over the domain. Once trained, LICO can generalize to unseen molecule properties simply via in-context prompting. LICO performs competitively on PMO, a challenging molecular optimization benchmark comprising 23 objective functions, and achieves state-of-the-art performance on its low-budget version PMO-1K.

ScholaWrite: A Dataset of End-to-End Scholarly Writing Process

✇cs.AI, q-bio.NC updates on arXiv.org
By: Khanh Chi Le · Linghe Wang · Minhwa Lee · Ross Volkov · Luan Tuyen Chau · Dongyeop Kang
23 October 2025 at 12:00
arXiv:2502.02904v4 Announce Type: replace-cross Abstract: Writing is a cognitively demanding activity that requires constant decision-making, heavy reliance on working memory, and frequent shifts between tasks of different goals. To build writing assistants that truly align with writers' cognition, we must capture and decode the complete thought process behind how writers transform ideas into final texts. We present ScholaWrite, the first dataset of end-to-end scholarly writing, tracing the multi-month journey from initial drafts to final manuscripts. We contribute three key advances: (1) a Chrome extension that unobtrusively records keystrokes on Overleaf, enabling the collection of realistic, in-situ writing data; (2) a novel corpus of full scholarly manuscripts, enriched with fine-grained annotations of cognitive writing intentions. The dataset includes \LaTeX-based edits from five computer science preprints, capturing nearly 62K text changes over four months; and (3) analyses and insights into the micro-dynamics of scholarly writing, highlighting gaps between human writing processes and the current capabilities of large language models (LLMs) in providing meaningful assistance. ScholaWrite underscores the value of capturing end-to-end writing data to develop future writing assistants that support, not replace, the cognitive work of scientists.

TinySQL: A Progressive Text-to-SQL Dataset for Mechanistic Interpretability Research

✇cs.AI, q-bio.NC updates on arXiv.org
By: Abir Harrasse · Philip Quirke · Clement Neo · Dhruv Nathawani · Luke Marks · Amir Abdullah
23 October 2025 at 12:00
arXiv:2503.12730v5 Announce Type: replace-cross Abstract: Mechanistic interpretability research faces a gap between analyzing simple circuits in toy tasks and discovering features in large models. To bridge this gap, we propose text-to-SQL generation as an ideal task to study, as it combines the formal structure of toy tasks with real-world complexity. We introduce TinySQL, a synthetic dataset, progressing from basic to advanced SQL operations, and train models ranging from 33M to 1B parameters to establish a comprehensive testbed for interpretability. We apply multiple complementary interpretability techniques, including Edge Attribution Patching and Sparse Autoencoders, to identify minimal circuits and components supporting SQL generation. We compare circuits for different SQL subskills, evaluating their minimality, reliability, and identifiability. Finally, we conduct a layerwise logit lens analysis to reveal how models compose SQL queries across layers: from intent recognition to schema resolution to structured generation. Our work provides a robust framework for probing and comparing interpretability methods in a structured, progressively complex setting.

Quantum Natural Language Processing: A Comprehensive Review of Models, Methods, and Applications

✇cs.AI, q-bio.NC updates on arXiv.org
By: Farha Nausheen · Khandakar Ahmed · M Imad Khan · Farina Riaz
23 October 2025 at 12:00
arXiv:2504.09909v2 Announce Type: replace-cross Abstract: In recent developments, deep learning methodologies applied to Natural Language Processing (NLP) have revealed a paradox: They improve performance but demand considerable data and resources for their training. Alternatively, quantum computing exploits the principles of quantum mechanics to overcome the computational limitations of current methodologies, thereby establishing an emerging field known as quantum natural language processing (QNLP). This domain holds the potential to attain a quantum advantage in the processing of linguistic structures, surpassing classical models in both efficiency and accuracy. In this paper, it is proposed to categorise QNLP models based on quantum computing principles, architecture, and computational approaches. This paper attempts to provide a survey on how quantum meets language by mapping state-of-the-art in this area, embracing quantum encoding techniques for classical data, QNLP models for prevalent NLP tasks, and quantum optimisation techniques for hyper parameter tuning. The landscape of quantum computing approaches applied to various NLP tasks is summarised by showcasing the specific QNLP methods used, and the popularity of these methods is indicated by their count. From the findings, it is observed that QNLP approaches are still limited to small data sets, with only a few models explored extensively, and there is increasing interest in the application of quantum computing to natural language processing tasks.

LongCodeBench: Evaluating Coding LLMs at 1M Context Windows

✇cs.AI, q-bio.NC updates on arXiv.org
By: Stefano Rando · Luca Romani · Alessio Sampieri · Luca Franco · John Yang · Yuta Kyuragi · Fabio Galasso · Tatsunori Hashimoto
23 October 2025 at 12:00
arXiv:2505.07897v3 Announce Type: replace-cross Abstract: Context lengths for models have grown rapidly, from thousands to millions of tokens in just a few years. The extreme context sizes of modern long-context models have made it difficult to construct realistic long-context benchmarks -- not only due to the cost of collecting million-context tasks but also in identifying realistic scenarios that require significant contexts. We identify code comprehension and repair as a natural testbed and challenge task for long-context models and introduce LongCodeBench (LCB), a benchmark to test LLM coding abilities in long-context scenarios. Our benchmark tests both the comprehension and repair capabilities of LCLMs in realistic and important settings by drawing from real-world GitHub issues and constructing QA (LongCodeQA) and bug fixing (LongSWE-Bench) tasks. We carefully stratify the complexity of our benchmark, enabling us to evaluate models across different scales -- ranging from Qwen2.5 14B Instruct to Google's flagship Gemini model. We find that long-context remains a weakness for all models, with performance drops such as from 29% to 3% for Claude 3.5 Sonnet, or from 70.2% to 40% for Qwen2.5. The LCB dataset is available publicly at https://huggingface.co/datasets/Steefano/LCB and the codebase to replicate the work on this paper at https://github.com/Zteefano/long-code-bench.

With Limited Data for Multimodal Alignment, Let the STRUCTURE Guide You

✇cs.AI, q-bio.NC updates on arXiv.org
By: Fabian Gr\"oger, Shuo Wen, Huyen Le, Maria Brbi\'c
23 October 2025 at 12:00
arXiv:2506.16895v2 Announce Type: replace-cross Abstract: Multimodal models have demonstrated powerful capabilities in complex tasks requiring multimodal alignment, including zero-shot classification and cross-modal retrieval. However, existing models typically rely on millions of paired multimodal samples, which are prohibitively expensive or infeasible to obtain in many domains. In this work, we explore the feasibility of building multimodal models with limited amount of paired data by aligning pretrained unimodal foundation models. We show that high-quality alignment is possible with as few as tens of thousands of paired samples$\unicode{x2013}$less than $1\%$ of the data typically used in the field. To achieve this, we introduce STRUCTURE, an effective regularization technique that preserves the neighborhood geometry of the latent space of unimodal encoders. Additionally, we show that aligning last layers is often suboptimal and demonstrate the benefits of aligning the layers with the highest representational similarity across modalities. These two components can be readily incorporated into existing alignment methods, yielding substantial gains across 24 zero-shot image classification and retrieval benchmarks, with average relative improvement of $51.6\%$ in classification and $91.8\%$ in retrieval tasks. Our results highlight the effectiveness and broad applicability of our framework for limited-sample multimodal learning and offer a promising path forward for resource-constrained domains.

ACT: Agentic Classification Tree

✇cs.AI, q-bio.NC updates on arXiv.org
By: Vincent Grari · Tim Arni · Thibault Laugel · Sylvain Lamprier · James Zou · Marcin Detyniecki
23 October 2025 at 12:00
arXiv:2509.26433v2 Announce Type: replace-cross Abstract: When used in high-stakes settings, AI systems are expected to produce decisions that are transparent, interpretable, and auditable, a requirement increasingly expected by regulations. Decision trees such as CART provide clear and verifiable rules, but they are restricted to structured tabular data and cannot operate directly on unstructured inputs such as text. In practice, large language models (LLMs) are widely used for such data, yet prompting strategies such as chain-of-thought or prompt optimization still rely on free-form reasoning, limiting their ability to ensure trustworthy behaviors. We present the Agentic Classification Tree (ACT), which extends decision-tree methodology to unstructured inputs by formulating each split as a natural-language question, refined through impurity-based evaluation and LLM feedback via TextGrad. Experiments on text benchmarks show that ACT matches or surpasses prompting-based baselines while producing transparent and interpretable decision paths.

Landscape of T-cell exhaustion heterogeneity and HBV integration in virus-related HCC revealed by whole-exome, transcriptome, and single-cell sequencing

✇Omics in Hepatocellular
By: Soon Kyu Lee · Jinyeong Lim · Joo Yeon Jhun · Jeonghyeon Moon · Hye Seon Kim · Jong Young Choi · Ho Joong Choi · Young Kyoung You · Ji Won Han · Pil Soo Sung · Kwon Yong Tak · Seung Kew Yoon · Woong-Yang Park · Mi-La Cho · Jeong Won Jang
20 October 2025 at 18:00

JHEP Rep. 2025 Jul 10;7(11):101518. doi: 10.1016/j.jhepr.2025.101518. eCollection 2025 Nov.

ABSTRACT

BACKGROUND & AIMS: To enhance our understanding of the tumor immune microenvironment (TIME) in hepatocellular carcinoma (HCC), we investigated the heterogeneity of T-cell exhaustion and its association with HBV integrations and direct oncogenic potential in HCC.

METHODS: We conducted a multi-omics analysis, including single-cell RNA sequencing, whole-exome sequencing, whole-transcriptome sequencing, and next-generation sequencing (NGS)-based HBV integration analysis, in eight patients with virus-related HCC. For validation, bulk RNA sequencing and NGS-based HBV integration analysis were performed in an independent cohort (n = 106).

RESULTS: Based on the expression scores of exhaustion markers in effector CD8+ T cells, patients were classified into high (n = 2) and low (n = 6) exhaustion groups (p <0.001). The high-exhaustion group exhibited higher clonal expansion (Gini index: 0.83 vs. 0.48, p = 0.006) and sharing of CD8+ T effector memory and cycling T cells with elevated exhaustion markers. This group also showed increased clonal expansion of CD4+ regulatory T cells and follicular helper T cells (p <0.001) with higher PDCD1 expression. In addition, the high-exhaustion group had higher TP53 mutation rates and signature scores for proliferation subtypes compared with the low-exhaustion group, who predominantly harbored TERT mutations. Moreover, the high-exhaustion group demonstrated more pronounced HBV integrations with elevated intrahepatic covalently closed circular DNA (cccDNA) and pregenomic (pg)RNA levels. Similarly, in the validation cohort, the high-exhaustion group (n = 28) demonstrated stronger proliferation subtype signatures (p <0.001), along with higher HBV integrations, S-fusion transcripts, and an increased intrahepatic viral reservoir (cccDNA/pgRNA) (p <0.05) compared with the low-exhaustion group (n = 78).

CONCLUSIONS: Our study revealed the heterogeneity in T-cell exhaustion in the TIME of HCC, along with differences in HBV integrations and molecular subtypes. These findings provide insight into the intricate relationship between high exhaustion, proliferation subtype, increased HBV integrations, and enhanced HBV-induced oncogenic potential in virus-related HCC.

IMPACT AND IMPLICATIONS: This study provides a comprehensive immune landscape of T-cell exhaustion using multi-omics analysis, offering critical insights into T cell heterogeneity in virus-related HCC. It establishes a strong association between higher HBV integration, enhanced oncogenic potential, T-cell exhaustion, and proliferation subtypes in HCC. Our results also establish a basis for personalized therapies tailored to the immune-exhaustion status within the TIME of each patient with HCC.

PMID:41113120 | PMC:PMC12529496 | DOI:10.1016/j.jhepr.2025.101518

Single-cell multi-omics analysis reveals cancer regulatory elements of transcriptional programs and clinical implications

✇Omics In Lung
By: Xiaowei Tang · Qiaoling Zhang · Zichu Shen · Jian Xiao · Minghao Li · Xiangyan Meng · Chenyi Wang · Guangze Zhang · Anhang Liu · Yuxin Yin
21 October 2025 at 18:00

Cell Death Dis. 2025 Oct 21;16(1):746. doi: 10.1038/s41419-025-08060-7.

ABSTRACT

The regulatory mechanisms governing transcriptional programs in the cancer genome remain elusive, particularly those concerning cell-type specificity. We carefully curated single-cell assay for transposase-accessible chromatin sequencing (scATAC-seq) and single-cell RNA sequencing (scRNA-seq) data from eight distinct carcinoma tissues, including breast, skin, colon, endometrium, lung, ovary, liver, and kidney. Using single-cell multi-omics analysis, we identified extensive open chromatin regions and constructed peak-gene link networks, which can reveal distinct cancer gene regulation and genetic risks. We further explored conserved epigenetic regulation across cell types within cancer and elucidated their functional implications. Moreover, we identified cell-type-associated transcription factors (TFs) that regulate key cellular functions, such as the TEAD family of TFs, which widely control cancer-related signaling pathways in tumor cells. In colon cancer, we further identified tumor-specific TFs that are more highly activated in tumor cells than in normal epithelial cells, including CEBPG, LEF1, SOX4, TCF7, and TEAD4, which are pivotal in driving malignant transcriptional programs and represent potential therapeutic targets, as corroborated by single-cell sequencing data from multiple sources and in vitro experiments. Our findings provide a comprehensive understanding of the regulatory dynamics underlying carcinomas and offer valuable insights into potential therapeutic interventions.

PMID:41120274 | PMC:PMC12541060 | DOI:10.1038/s41419-025-08060-7

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