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Normal view

Received today — 7 October 2026 ⏭

Transketolase-like 1 potentiates PD-1 blockade in hepatocellular carcinoma by glycolysis to prime dendritic cell lactylation

✇Omics in Hepatocellular
By: Hengsong Cao · Tian Huang · Yue Chai · Zhengqing Lu · Shipeng Dai · Danyang Xu · Yanshu He · Na Yu · Yuliang Wang · Ziyuan Liu · Yidong Xia · Jie Zhao · Hongyu Wang · Dawei Rong · Yuchen Xie · Chongyu Wang · Pengyu Chen · Juyue Zhou · Li Liu · Zhuozheng Li · Hanyuan Liu · Xiao Li · Xuehao Wang · Weiwei Tang · Yongxiang Xia
27 September 2026 at 18:00

Signal Transduct Target Ther. 2026 Sep 28;11(1):418. doi: 10.1038/s41392-026-02875-2.

ABSTRACT

Hepatocellular carcinoma (HCC) exhibits a suboptimal response to immune checkpoint blockade (ICB) therapy; to overcome this resistance, we aimed to delineate key immune resistance factors via multi-omics analysis, develop strategies to block their immunosuppressive axes, and engineer a targeted nanosystem to enhance immunotherapy efficacy against PD-1 resistance in HCC. Using transcriptomic and proteomic data from anti-PD-1-treated HCC patients, along with functional validation in murine models and mechanistic molecular and cell biology studies, we identified transketolase-like 1 (TKTL1) as a dual-nature biomarker where overexpression predicted poor baseline prognosis yet enhanced response to ICB. Mechanistically, TKTL1 diverts glucose flux into glycolysis rather than pentose phosphate pathway (PPP), recruiting USP9X to deubiquitinate and stabilize HIF-1α, which upregulates HK2 to amplify glycolytic output and lactate accumulation. This metabolic rewiring orchestrates dual immunosuppressive circuits through HIF-1α-driven CCL4 secretion recruiting PD-L1high dendritic cells (DCs), coupled with lactate-induced TRIM28K408 lactylation that stabilizes PD-L1 by blocking ubiquitin-mediated degradation. We engineered a hepatoma-membrane-coated MnO₂ nanosystem (CQLH) co-delivering a TKTL1 inhibitor and lactate oxidase, which disrupted the TKTL1-HIF-1α-HK2 axis, depleted lactate, and reprogrammed the tumor microenvironment, thereby enhanced anti-PD-1 therapy to suppress tumor growth, especially in TKTL1high tumors. These findings define a critical "TKTL1-glycolysis-lactate-DC" axis driving anti-PD-1 sensitivity in HCC, position TKTL1 as both a potential biomarker for ICB response and a tractable therapeutic target, and demonstrate that the targeted CQLH nanosystem overcomes resistance and enhances anti-PD-1 efficacy, offering a precision immunotherapeutic strategy for TKTL1high HCC.

PMID:42802226 | PMC:PMC13616917 | DOI:10.1038/s41392-026-02875-2

Received — 15 September 2026 ⏭

Do LLMs Trust the Accuser or the Accusation? Measuring Belief Shifts in Werewolf

✇cs.AI, q-bio.NC updates on arXiv.org
By: Yu-Yu Yang · Ti-Rong Wu · Hung Guei · Hsing-Yu Chen · I-Chen Wu
14 September 2026 at 12:00
arXiv:2609.12446v1 Announce Type: new Abstract: Social-deduction games such as Werewolf are increasingly used to evaluate LLM agents, but existing evaluations often rely on final game outcomes. We propose a belief-shift evaluation benchmark in Werewolf for analyzing communication skills through belief updating. Using LLM-played games, we annotate suspicion and accusation messages and measure how an observing village-side model's beliefs change after each message. We evaluate 40 open-weight LLM configurations on 1,224 annotated messages. Our results show that larger models better distinguish true wolves from villagers based on game history, but accusations still strongly influence their beliefs. Models become more suspicious of the accused target and less suspicious of the accuser, especially when the accuser is trusted, even if the accuser is wolf-aligned. Larger models better resist accusations from accusers they already distrust. Overall, our findings suggest that current open-weight LLMs up to 120B parameters still struggle to integrate accusation content with source trust in strategic communication. Our benchmark and code are available at https://rlg.iis.sinica.edu.tw/papers/werewolf-accusation-benchmark.

Who Pays for Open Review? Visible Author Reputation and Its Effect on Ratings

✇cs.AI, q-bio.NC updates on arXiv.org
By: Qinghua Zhao · Xinyu Chen · Yanhui Yang · Tengfeng Sun · Junfeng Liu · Zhongfeng Kang
14 September 2026 at 12:00
arXiv:2609.11983v1 Announce Type: cross Abstract: An OpenReview bug in November 2025 broke anonymity at several conferences and prompted calls for open review, which motivate us to ask what shifting from blind to open would mean for authors. Analyzing over 18,000 reviewed submissions to ICLR 2026, split into de facto open and blind groups by arXiv preprint timing, we find that ratings rise with author reputation under both mechanisms, with a steeper slope under open review that is statistically significant, and that the open-blind difference is concentrated at the borderline ratings. The pattern holds across five reputation proxies (including institution, h-index, and citation count), three author-aggregation rules, and five definitions of the open window. A controlled simulation with five AI models as reviewers, holding the manuscript fixed and varying the author reputation, reproduces the effect. With claude-opus-5 as the reviewer, for example, rating rises by 0.5 points as the author moves from low to high reputation.

MInTRL: Off-policy Intervention can boost On-policy RL

✇cs.AI, q-bio.NC updates on arXiv.org
By: Mingyu Chen · Yefan Tao · Gerald Friedland · Xuezhou Zhang · Chris Kong
14 September 2026 at 12:00
arXiv:2609.12419v1 Announce Type: cross Abstract: Reinforcement learning with verifiable rewards is typically performed on-policy, keeping training data close to the current policy but limiting learning to trajectories that the policy can discover itself. Off-policy methods such as supervised fine-tuning, on the other hand, can leverage external knowledge beyond the base model's capabilities, but may suffer from large distribution shift. The key challenge is thus to expand exploration without sacrificing learnability. In this work, we introduce Minimal Intervention Reinforcement Learning (MInTRL), which expands the exploration frontier through sparse, local interventions in otherwise on-policy rollouts. During generation, a judge-intervention policy periodically reviews the current policy's output, replaces erroneous suffixes with short corrections, and immediately returns control to the policy. During training, MInTRL adopts a sequence-level advantage-regression objective that eliminates the need for importance sampling. We show that sparse, local interventions can substantially improve coverage beyond finite-budget on-policy sampling while preserving the overall on-policy nature of the resulting trajectories. Across math and code benchmarks, MInTRL consistently outperforms standard on-policy and off-policy baselines. Ablations show that MInTRL remains effective with self-intervention and across different judge policies, while performance peaks at moderate intervention intensity, highlighting the importance of intervening minimally. These results establish minimal intervention as an effective paradigm for enhancing on-policy RL.

Lumina-OmniLV: A Unified Multimodal Framework for General Low-Level Vision

✇cs.AI, q-bio.NC updates on arXiv.org
By: Yuandong Pu · Le Zhuo · Kaiwen Zhu · Liangbin Xie · Wenlong Zhang · Xiangyu Chen · Peng Gao · Yu Qiao · Chao Dong · Yihao Liu
14 September 2026 at 12:00
arXiv:2504.04903v3 Announce Type: replace-cross Abstract: We present Lunima-OmniLV (abbreviated as OmniLV), a universal multimodal multi-task framework for low-level vision that addresses over 100 sub-tasks across four major categories: image restoration, image enhancement, weak-semantic dense prediction, and stylization. OmniLV leverages both textual and visual prompts to offer flexible and user-friendly interactions. Built on Diffusion Transformer (DiT)-based generative priors, our framework supports arbitrary resolutions -- achieving optimal performance at 1K resolution -- while preserving fine-grained details and high fidelity. Through extensive experiments, we demonstrate that separately encoding text and visual instructions, combined with co-training using shallow feature control, is essential to mitigate task ambiguity and enhance multi-task generalization. Our findings also reveal that integrating high-level generative tasks into low-level vision models can compromise detail-sensitive restoration. These insights pave the way for more robust and generalizable low-level vision systems.

Advanced and underlying therapeutic strategies in transformed small cell lung cancer

✇Omics In Lung
By: Mingfeng Wei · Zheng Li · Kaiyuan Zhu · Shixiang Guo · Lefei Hu · Fuzhi Yang · Xiaoyu Chen · Xuelin Zhang · Shuai Jiang · Xunxia Zhu · Xiaoyong Shen
11 September 2026 at 18:00

Front Med (Lausanne). 2026 Aug 27;13:1865050. doi: 10.3389/fmed.2026.1865050. eCollection 2026.

ABSTRACT

Transformed small-cell lung cancer (T-SCLC) is a clinically important form of histologic transformation and a mechanism of acquired resistance in non-small-cell lung cancer (NSCLC). It is associated with poor prognosis, with a median overall survival of only about 9-13 months. This review summarizes recent advances in the mechanisms, diagnosis, monitoring, and treatment of T-SCLC. Repeat biopsy remains the gold standard for confirming histologic transformation, whereas molecular profiling and liquid biopsy may facilitate early detection and longitudinal disease monitoring. Platinum-etoposide remains the most commonly used clinical standard after transformation, but its benefit is typically transient and durable disease control remains uncommon. Continuation of EGFR tyrosine kinase inhibitors combined with chemotherapy may prolong progression-free survival in selected patients but has not consistently improved overall survival. Anti-angiogenic therapy, particularly anlotinib, and chemo-immunotherapy have shown encouraging activity in selected patients, while emerging strategies targeting DLL3, MYC, SOX2, and epigenetic regulators may broaden the therapeutic landscape. Prospective studies integrating repeat tissue sampling, comprehensive genomic profiling, biomarker-guided patient stratification, pharmacogenomics, functional drug-sensitivity testing where feasible, and integrated multi-omics approaches are needed to advance molecularly guided and individualized treatment for T-SCLC.

PMID:42724635 | PMC:PMC13560167 | DOI:10.3389/fmed.2026.1865050

Narrative review of the staging classification controversy in stage N3 small cell lung cancer: from the perspective of overlapping Veterans Administration Lung Study Group and International Association for the Study of Lung Cancer definitions

✇Omics In Lung
By: Xinyu Chen · Qilin Wang · Juncai Ye · Xueping Yang · Jiahao Chen · Guangzeng Zhou · Chuanyu You · Tian Xu · Yan Gui
11 September 2026 at 18:00

J Thorac Dis. 2026 Aug 31;18(8):950. doi: 10.21037/jtd-2026-1704. Epub 2026 Aug 28.

ABSTRACT

BACKGROUND AND OBJECTIVE: Traditionally, two primary systems have been employed for staging small cell lung cancer (SCLC): the Veterans Administration Lung Study Group (VALG) system and the International Association for the Study of Lung Cancer (IASLC) tumor, node, metastasis (TNM) system. The term "limited disease" is defined differently: VALG characterizes it as disease encompassed within a single tolerable radiation field, while IASLC defines it as the lack of distant metastases (M0). Patients with N3 disease frequently satisfy VALG extensive-stage (ES) criteria while meeting IASLC limited-stage (LS) criteria, resulting in a notable staging discrepancy. Therefore, this review aims to clarify the clinical challenges posed by this staging overlap and provide insights for standardizing staging terminology and optimizing therapeutic decision-making in N3 SCLC.

METHODS: A narrative review utilizing a systematized search strategy was conducted. While strict adherence to PRISMA guidelines was not pursued because the extensive heterogeneity of the literature precluded a formal meta-analysis, rigorous search criteria were applied to minimize selection bias. Databases including PubMed, Web of Science, Embase, the Cochrane Library, and China National Knowledge Infrastructure (CNKI) were searched for literature from January 2000 to March 2026. Studies examining stage N3 SCLC, spatial metastatic burden, and definitional inconsistencies between the VALG and IASLC staging systems were analyzed to assess their effects on treatment dosimetry, systemic therapy, and survival outcomes.

KEY CONTENT AND FINDINGS: The staging overlap in N3 SCLC leads to heterogeneous clinical management depending on its spatial metastatic burden, and this highly variable cohort can be stratified into distinct prognostic subgroups based on the anatomical distribution (single-region vs. multi-region) of the involved lymph nodes.

CONCLUSIONS: These findings should guide clinical trial design and terminology. Clinical decision-making must transcend historical paradigms and technical constraints. Future strategies must incorporate spatial evaluations of metastatic burden alongside innovative multimodal tools, such as artificial intelligence (AI) and multi-omics, to facilitate tailored therapy for SCLC.

PMID:42724560 | PMC:PMC13559235 | DOI:10.21037/jtd-2026-1704

Received — 13 September 2026 ⏭

Advanced and underlying therapeutic strategies in transformed small cell lung cancer

✇(Multiomics OR Omics) AND (Lung OR gastric OR Hepatocellular)
By: Mingfeng Wei · Zheng Li · Kaiyuan Zhu · Shixiang Guo · Lefei Hu · Fuzhi Yang · Xiaoyu Chen · Xuelin Zhang · Shuai Jiang · Xunxia Zhu · Xiaoyong Shen
11 September 2026 at 18:00

Front Med (Lausanne). 2026 Aug 27;13:1865050. doi: 10.3389/fmed.2026.1865050. eCollection 2026.

ABSTRACT

Transformed small-cell lung cancer (T-SCLC) is a clinically important form of histologic transformation and a mechanism of acquired resistance in non-small-cell lung cancer (NSCLC). It is associated with poor prognosis, with a median overall survival of only about 9-13 months. This review summarizes recent advances in the mechanisms, diagnosis, monitoring, and treatment of T-SCLC. Repeat biopsy remains the gold standard for confirming histologic transformation, whereas molecular profiling and liquid biopsy may facilitate early detection and longitudinal disease monitoring. Platinum-etoposide remains the most commonly used clinical standard after transformation, but its benefit is typically transient and durable disease control remains uncommon. Continuation of EGFR tyrosine kinase inhibitors combined with chemotherapy may prolong progression-free survival in selected patients but has not consistently improved overall survival. Anti-angiogenic therapy, particularly anlotinib, and chemo-immunotherapy have shown encouraging activity in selected patients, while emerging strategies targeting DLL3, MYC, SOX2, and epigenetic regulators may broaden the therapeutic landscape. Prospective studies integrating repeat tissue sampling, comprehensive genomic profiling, biomarker-guided patient stratification, pharmacogenomics, functional drug-sensitivity testing where feasible, and integrated multi-omics approaches are needed to advance molecularly guided and individualized treatment for T-SCLC.

PMID:42724635 | PMC:PMC13560167 | DOI:10.3389/fmed.2026.1865050

Narrative review of the staging classification controversy in stage N3 small cell lung cancer: from the perspective of overlapping Veterans Administration Lung Study Group and International Association for the Study of Lung Cancer definitions

✇(Multiomics OR Omics) AND (Lung OR gastric OR Hepatocellular)
By: Xinyu Chen · Qilin Wang · Juncai Ye · Xueping Yang · Jiahao Chen · Guangzeng Zhou · Chuanyu You · Tian Xu · Yan Gui
11 September 2026 at 18:00

J Thorac Dis. 2026 Aug 31;18(8):950. doi: 10.21037/jtd-2026-1704. Epub 2026 Aug 28.

ABSTRACT

BACKGROUND AND OBJECTIVE: Traditionally, two primary systems have been employed for staging small cell lung cancer (SCLC): the Veterans Administration Lung Study Group (VALG) system and the International Association for the Study of Lung Cancer (IASLC) tumor, node, metastasis (TNM) system. The term "limited disease" is defined differently: VALG characterizes it as disease encompassed within a single tolerable radiation field, while IASLC defines it as the lack of distant metastases (M0). Patients with N3 disease frequently satisfy VALG extensive-stage (ES) criteria while meeting IASLC limited-stage (LS) criteria, resulting in a notable staging discrepancy. Therefore, this review aims to clarify the clinical challenges posed by this staging overlap and provide insights for standardizing staging terminology and optimizing therapeutic decision-making in N3 SCLC.

METHODS: A narrative review utilizing a systematized search strategy was conducted. While strict adherence to PRISMA guidelines was not pursued because the extensive heterogeneity of the literature precluded a formal meta-analysis, rigorous search criteria were applied to minimize selection bias. Databases including PubMed, Web of Science, Embase, the Cochrane Library, and China National Knowledge Infrastructure (CNKI) were searched for literature from January 2000 to March 2026. Studies examining stage N3 SCLC, spatial metastatic burden, and definitional inconsistencies between the VALG and IASLC staging systems were analyzed to assess their effects on treatment dosimetry, systemic therapy, and survival outcomes.

KEY CONTENT AND FINDINGS: The staging overlap in N3 SCLC leads to heterogeneous clinical management depending on its spatial metastatic burden, and this highly variable cohort can be stratified into distinct prognostic subgroups based on the anatomical distribution (single-region vs. multi-region) of the involved lymph nodes.

CONCLUSIONS: These findings should guide clinical trial design and terminology. Clinical decision-making must transcend historical paradigms and technical constraints. Future strategies must incorporate spatial evaluations of metastatic burden alongside innovative multimodal tools, such as artificial intelligence (AI) and multi-omics, to facilitate tailored therapy for SCLC.

PMID:42724560 | PMC:PMC13559235 | DOI:10.21037/jtd-2026-1704

Deep learning combined habitat radiomics analysis of central lymph node metastasis in papillary thyroid carcinoma

✇npj Digital Medicine
By: Tianhan Zhou · Yang Zhou · Zhongkai Ni · Hao Fang · Fan Wu · Yangyang Xie · Xinyang Song · Sihan Sun · Xianfeng Wang · Xiangfeng Lin · Dong Guo · Lihua Hong · Xiaogang Qi · Chang Su · Jie Wang · Yu Chen · Quanbao Zhang · Jinwang Ding · Lei Xu · Hai Huang
12 September 2026 at 08:00

npj Digital Medicine, Published online: 12 September 2026; doi:10.1038/s41746-026-03203-2

Deep learning combined habitat radiomics analysis of central lymph node metastasis in papillary thyroid carcinoma
Received — 10 September 2026 ⏭

BRACE: Anchored Bellman-Residual Correction for Stale Critics in Asynchronous RL

✇cs.AI, q-bio.NC updates on arXiv.org
By: Guanqun Zhao · Zijun Xie · Binbin Zheng · Jiafeng Lu · Enlei Gong · Zeyu Chen
10 September 2026 at 12:00
arXiv:2609.09783v1 Announce Type: cross Abstract: Asynchronous reinforcement learning has become the standard way to scale training for language models, but the resulting policy lag biases the critic toward the stale behavior policy. Existing work on asynchronous LLM training corrects the actor and leaves this bias unaddressed, while the off-policy value correction of classical RL does not carry over to long-horizon agentic tasks, since a short correction horizon leaves the regression target free of the reward and a long one lets the product of importance ratios drift exponentially with the trajectory length. We propose BRACE, an anchored Bellman-residual correction for stale value models. BRACE bounds the correction horizon to a prefix of policy tokens and anchors a constant-weight Monte-Carlo tail beyond it, which separates policy correction from reward propagation. BRACE improves mean@1 on BrowseComp-Plus by $2.4\%$ over the strongest baseline, runs $2.46\times$ faster per step than synchronous training, and remains stable $50$ updates off-policy.

How Fragile Is Safety Alignment at Frontier Scale? A Single-Direction Attack on a 320B MoE

✇cs.AI, q-bio.NC updates on arXiv.org
By: Yi Shi · Tanyu Chen · Kai Shen
10 September 2026 at 12:00
arXiv:2609.09793v1 Announce Type: cross Abstract: Directional ablation removes an aligned language model's ability to refuse by projecting a single "refusal direction" out of the weights that write the residual stream. It needs no gradient-based training and no optimization, only a few hundred contrastive prompts, which makes it the canonical white-box attack on open-weight alignment. However, it has been established only on dense models up to roughly 70B parameters. We study whether it survives the shift to frontier mixture-of-experts (MoE) models whose residual streams are no longer a single tensor and whose weights ship quantized. We apply it to GLM-5.3-Flash (320B parameters, 288 routed experts, a four-wide hyper-connection residual, block-FP8). The attack survives the architecture, but what it reaches is no longer where a reader of the original recipe would look for it. Editing the attention, dense and routed-expert writers on their own removes 0.039, 0.016 and 0.148 of refusal respectively; editing all three together removes 0.776. As a result, 74% of the effect exists only under the joint intervention. The part the conventional recipe reaches by module-name matching accounts for 0.066 of that 0.776, which is why it fails silently on an MoE. The effect does not follow from removing just any direction: ablating a random direction orthogonal to it leaves refusal unchanged. A category-concentrated residue survives every edit we tried: subspaces fitted on violence, sexual content and hate leave measurable refusal at every rank from 1 to 12. We report the method, the 41-89 percentage-point reductions it achieves across seven harmful benchmarks with no detected change in capability, and the boundary where it stops.

GANDR: Claim Auditing for Verifiable Legal Answer Generation

✇cs.AI, q-bio.NC updates on arXiv.org
By: Chen Qian · Yimeng Wang · Yu Chen · Lingfei Wu · Andreas Stathopoulos
10 September 2026 at 12:00
arXiv:2609.10293v1 Announce Type: cross Abstract: In high-stakes domains such as legal practice, a language-model answer is only useful to the extent that a reader can verify each claim against the source the system cites. Current grounded-generation pipelines score the answer as a whole, so a correct conclusion can rest on fabricated or loosely matched citations and still score well. Closing this gap requires both a system built for per-claim verification and an evaluation that measures it. We introduce GANDR (Grounded ANswer DRafter), a two-agent system in which a Drafter writes an answer in a structured legal-reasoning format and a separate Critic, with the same view as a human verifier, audits each claim against its cited source and emits a per-claim audit trace on every round. We pair it with a strict correctness criterion requiring every citation to resolve to a passage the retriever returned. On a 185-item legal benchmark where all six systems share one backbone, one retrieval surface, and one citation instruction, GANDR ranks first on every primary metric, reaching 70.8% strict accuracy and leading the strongest baseline by 11.3 points (p

MOONWALK: Mediating Operations with Intent-Evidence-Action Alignment Across Junior-Supervisor Review Workflows in Animation/VFX Pre-Production

✇cs.AI, q-bio.NC updates on arXiv.org
By: Shih-Yu Lai · Wen-Fan Wang · Sai Ling · Shaune Jan · Bing-Yu Chen · Xiang Anthony Chen
10 September 2026 at 12:00
arXiv:2609.10385v1 Announce Type: cross Abstract: Animation and VFX pre-production review requires teams to translate loosely specified creative intent--briefs, evolving specifications, heterogeneous references, and verbal decisions--into revisions that junior artists can execute without repeated clarification. In practice, criteria drift across iterations, review judgments lose their evidential basis, and the reasoning behind a request rarely survives the senior-junior handoff. We contribute a design framework for intent-evidence-action alignment: intent is articulated into a shared project record, judgments are anchored to grounded evidence, and authorized decisions are converted into clear revision tasks tied directly to reference notes. We instantiate this framework in MOONWALK, a professional pre-production review system comprising a shared intent record, reference/specification anchoring, structured work-in-progress comparison, and supervisor-authorized action planning. In this workflow, AI handles administrative coordination--flagging missing context and organizing notes--while artists retain full creative direction. An in-studio study with professional practitioners compares MOONWALK with a chat-only (chatbot) interface using matched production materials, while participants' existing workflows provide a retrospective ecological baseline. Results indicate stronger intent alignment, decision traceability, and checklist executability, while also showing that aesthetic authority and final prioritization must remain with practitioners. The evaluation establishes the value of the integrated structured workflow over unstructured conversational AI chatbot. Code: https://github.com/Akinesia112/Moonwalk/tree/english-version

S1P-TREM2 axis protects immunosuppressive neutrophils from ferroptosis to promote tumour progression in hepatocellular carcinoma

✇Omics in Hepatocellular
By: Jun Ma · Tong Wu · Diyu Chen · Can Zhu · Shanhe Huang · Keyi Du · Chuanhui Peng · Junru Chen · Yunhao Chen · Haiyang Xie · Feng Zhang · Jianzhong Chen · Shusen Zheng · Jian Wu
7 September 2026 at 18:00

Gut. 2026 Sep 7:gutjnl-2025-337414. doi: 10.1136/gutjnl-2025-337414. Online ahead of print.

ABSTRACT

BACKGROUND: Neutrophils are increasingly recognised as immunosuppressive drivers of hepatocellular carcinoma (HCC), yet their persistence in the oxidative, lipid-rich tumour microenvironment remains poorly understood.

OBJECTIVE: To elucidate the metabolic and molecular programmes that enable tumour-associated neutrophils (TANs) to resist ferroptosis and sustain immunosuppression in HCC.

DESIGN: We employed human HCC samples, multiple murine HCC models, transcriptomic and lipidomic profiling, genetic loss-of-function systems and therapeutic interventions. Ferroptosis sensitivity, lipid metabolic rewiring and immunological consequences of TANs were systematically evaluated across models and validated in patient datasets and biospecimens.

RESULTS: TANs in human HCC and mouse models exhibit pronounced lipid accumulation and oxidative stress compared with peripheral neutrophils. Multi-omic profiling revealed that TANs are enriched for lipid-binding gene programmes and undergo rewiring towards sphingolipid and unsaturated fatty acid metabolism. We identified triggering receptor expressed on myeloid cells 2 (TREM2) as a key lipid-sensing receptor selectively expressed in TANs. Functional deletion of TREM2 reprogrammed the tumour immune microenvironment, restoring CD8+ T cell activity and suppressing HCC progression. Mechanistically, tumour-derived sphingosine-1-phosphate (S1P) activates TREM2, triggering nuclear factor erythroid 2-related factor 2 (NRF2)-mediated transcription of glutathione peroxidase 4 (GPX4) and solute carrier family 7 member 11 (SLC7A11), thereby promoting ferroptosis resistance. TREM2 expression is transcriptionally induced by granulocyte-macrophage colony-stimulating factor-signal transducer and activator of transcription 3 (GM-CSF-STAT3) signalling. Genetic deletion of TREM2, clustered regularly interspaced short palindromic repeats/CRISPR-associated protein 9 (CRISPR/Cas9)-mediated knockout of sphingosine kinase 1/2 (SPHK1/2) in tumour cells, or pharmacological inhibition of S1P synthesis disrupts this protective lipid-immune circuit, sensitises TANs to ferroptosis and restricts tumour growth. Therapeutically, a peptide-based TREM2 inhibitor reprogrammes TANs, restores CD8+ T cell function and enhances anti-programmed cell death protein 1 (PD-1) immunotherapy efficacy. Clinically, TREM2+ polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs) are enriched in HCC tumours, correlate with SPHK1/2 expression and T cell dysfunction and associate with poor patient prognosis.

CONCLUSION: Our study uncovers the S1P-TREM2-NRF2 axis as a critical metabolic-immune circuit that preserves neutrophil survival and immunosuppressive function in HCC. Targeting this lipid-dependent ferroptosis resistance pathway offers a promising therapeutic strategy to overcome immunotherapy resistance in liver cancer.

PMID:42705697 | DOI:10.1136/gutjnl-2025-337414

S1P-TREM2 axis protects immunosuppressive neutrophils from ferroptosis to promote tumour progression in hepatocellular carcinoma

✇(Multiomics OR Omics) AND (Pancreatic)
By: Jun Ma · Tong Wu · Diyu Chen · Can Zhu · Shanhe Huang · Keyi Du · Chuanhui Peng · Junru Chen · Yunhao Chen · Haiyang Xie · Feng Zhang · Jianzhong Chen · Shusen Zheng · Jian Wu
7 September 2026 at 18:00

Gut. 2026 Sep 7:gutjnl-2025-337414. doi: 10.1136/gutjnl-2025-337414. Online ahead of print.

ABSTRACT

BACKGROUND: Neutrophils are increasingly recognised as immunosuppressive drivers of hepatocellular carcinoma (HCC), yet their persistence in the oxidative, lipid-rich tumour microenvironment remains poorly understood.

OBJECTIVE: To elucidate the metabolic and molecular programmes that enable tumour-associated neutrophils (TANs) to resist ferroptosis and sustain immunosuppression in HCC.

DESIGN: We employed human HCC samples, multiple murine HCC models, transcriptomic and lipidomic profiling, genetic loss-of-function systems and therapeutic interventions. Ferroptosis sensitivity, lipid metabolic rewiring and immunological consequences of TANs were systematically evaluated across models and validated in patient datasets and biospecimens.

RESULTS: TANs in human HCC and mouse models exhibit pronounced lipid accumulation and oxidative stress compared with peripheral neutrophils. Multi-omic profiling revealed that TANs are enriched for lipid-binding gene programmes and undergo rewiring towards sphingolipid and unsaturated fatty acid metabolism. We identified triggering receptor expressed on myeloid cells 2 (TREM2) as a key lipid-sensing receptor selectively expressed in TANs. Functional deletion of TREM2 reprogrammed the tumour immune microenvironment, restoring CD8+ T cell activity and suppressing HCC progression. Mechanistically, tumour-derived sphingosine-1-phosphate (S1P) activates TREM2, triggering nuclear factor erythroid 2-related factor 2 (NRF2)-mediated transcription of glutathione peroxidase 4 (GPX4) and solute carrier family 7 member 11 (SLC7A11), thereby promoting ferroptosis resistance. TREM2 expression is transcriptionally induced by granulocyte-macrophage colony-stimulating factor-signal transducer and activator of transcription 3 (GM-CSF-STAT3) signalling. Genetic deletion of TREM2, clustered regularly interspaced short palindromic repeats/CRISPR-associated protein 9 (CRISPR/Cas9)-mediated knockout of sphingosine kinase 1/2 (SPHK1/2) in tumour cells, or pharmacological inhibition of S1P synthesis disrupts this protective lipid-immune circuit, sensitises TANs to ferroptosis and restricts tumour growth. Therapeutically, a peptide-based TREM2 inhibitor reprogrammes TANs, restores CD8+ T cell function and enhances anti-programmed cell death protein 1 (PD-1) immunotherapy efficacy. Clinically, TREM2+ polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs) are enriched in HCC tumours, correlate with SPHK1/2 expression and T cell dysfunction and associate with poor patient prognosis.

CONCLUSION: Our study uncovers the S1P-TREM2-NRF2 axis as a critical metabolic-immune circuit that preserves neutrophil survival and immunosuppressive function in HCC. Targeting this lipid-dependent ferroptosis resistance pathway offers a promising therapeutic strategy to overcome immunotherapy resistance in liver cancer.

PMID:42705697 | DOI:10.1136/gutjnl-2025-337414

Received — 27 May 2026 ⏭

LC-ERD: Mining Latent Logic for Self-Evolving Reasoning via Consistency-Regulated Reward Decomposition

✇cs.AI, q-bio.NC updates on arXiv.org
By: Yanyu Chen · Jiyue Jiang · Dianzhi Yu · Zheng Wu · Jiahong Liu · Jiaming Han · Xiao Guo · Jinhu Qi · Yu Li · Yifei Zhang · Irwin King
26 May 2026 at 12:00
arXiv:2605.24005v1 Announce Type: new Abstract: The evolution of Large Language Model (LLM) reasoning is bottlenecked by the scarcity of high-quality process data. While self-alignment via endogenous rewards offers a solution, mining valid supervision faces three challenges: (1) Label Noise via Mimetic Bias, where rewards prioritize statistical likelihood over logical truth, creating a "correctness illusion" that masks compounding errors; (2) Coarse-Grained Supervision, where sparse global outcomes (e.g., in GRPO) fail to provide granular guidance, treating reasoning chains as monolithic; and (3) Distributional Collapse, where signals fail to generalize without amplifying pre-training biases. To address these, we introduce LC-ERD (Logic-Consistent Endogenous Reward Decomposition), a framework framing self-alignment as latent structure mining. We derive a Variational Logic Potential by aggregating consensus from the model's Latent Logic Expertise (LLE) to denoise the reasoning manifold, and introduce a Multi-Agent Value Decomposition protocol based on the IGM principle to quantify individual step utility. Experiments show LC-ERD delivers a robust self-evolution path, uncovering trade-offs between logic consistency and accuracy while identifying high-value reasoning patterns missed by standard rewards. Our code is available at https://github.com/Reinhardmannn/LC-ERD.

STREAM: A Data-Centric Framework for Mining High-Value Task-Oriented Dialogues from Streaming Media

✇cs.AI, q-bio.NC updates on arXiv.org
By: Liang Xue · Haoyu Liu · Cheng Wang · Pengyu Chen · Haozhuo Zheng · Yang Liu
26 May 2026 at 12:00
arXiv:2605.25162v1 Announce Type: cross Abstract: Large language models for vertical domains are bottlenecked by the scarcity of complex, domain-specific task-oriented dialogues. Existing data acquisition pipelines face a persistent trilemma: expert annotation is expensive, real-world service conversations are constrained by privacy and commercial restrictions, and static corpora quickly become temporally stale. We propose Stream, a data-centric framework that leverages publicly available streaming media (live streams and short videos) to synthesize high-value service dialogues at scale. Stream mines authentic interaction signals from noisy streams and synthesizes conversations by integrating role-grounded persona construction with Conversational Blueprint construction; it further adopts retrieval-augmented generation (RAG) to support knowledge-aware responses. Based on Stream, we release StreamDial, a large-scale multi-domain dataset covering Automotive, Restaurant, and Hotel. StreamDial contains 87,498 dialogue sessions and 1,497,320 turns in total, with an average of 17.11 turns per session and a comparable scale across domains. Each session is organized as a structured quadruplet $\langle P_u, P_a, B, H \rangle$ that pairs dialogue history with explicit user/agent personas and a Conversational Blueprint, capturing realistic service behaviors such as requirement mining, constraint conflicts, negotiation, and recovery. Evaluations with automatic judges and downstream tasks show that StreamDial improves intrinsic dialogue quality over strong baselines, and models trained with StreamDial improve Dialogue State Tracking across backbones; we further report a completed human-evaluation set and encouraging multilingual transfer on Qwen3-8B under a controlled training budget. The data is released in https://github.com/hitxueliang/DialogDataSetBySTREAM.
  • ✇cs.AI, q-bio.NC updates on arXiv.org
  • Extreme Region Policy Distillation Changyu Chen · Xiting Wang · Rui Yan
    arXiv:2605.25582v1 Announce Type: cross Abstract: Reinforcement learning for large language models faces a fundamental trade-off between sample efficiency and asymptotic performance: strictly on-policy methods discard trajectories after a single update, while off-policy reuse introduces distribution mismatch that existing trust-region techniques mitigate primarily by enforcing conservative optimization, often leaving rich training signals underutilized. To investigate this, we perform extensive
     
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Extreme Region Policy Distillation

✇cs.AI, q-bio.NC updates on arXiv.org
By: Changyu Chen · Xiting Wang · Rui Yan
26 May 2026 at 12:00
arXiv:2605.25582v1 Announce Type: cross Abstract: Reinforcement learning for large language models faces a fundamental trade-off between sample efficiency and asymptotic performance: strictly on-policy methods discard trajectories after a single update, while off-policy reuse introduces distribution mismatch that existing trust-region techniques mitigate primarily by enforcing conservative optimization, often leaving rich training signals underutilized. To investigate this, we perform extensive off-policy updates on fixed data. Our experiments reveal that aggressive multi-step optimization brings rapid initial gains, but excessive updates cause trajectory probabilities to deviate and entropy to collapse, with performance plateauing early. Tightening KL constraints merely lowers the ceiling without resolving the degradation. This motivates Extreme Region Policy Distillation (ERPD), a two-stage framework that decouples sample efficiency from KL efficiency. The first stage performs weakly constrained off-policy optimization on fixed data to maximally extract training signals. The resulting policy provides token-level supervision. In the second stage, we distill these signals into the base policy under trust-region constraints, filtering harmful drift while preserving useful signals. The distilled policy achieves comparable or better performance with substantially smaller KL divergence, indicating that much of the first-stage divergence was spent on unnecessary drift rather than genuine improvement. Crucially, ERPD accommodates both strong and weak teachers: when aggressive optimization yields no stronger policy, even degenerate teachers provide effective supervision via alternative signal construction strategies. We validate ERPD on mathematical reasoning, showing gains for strong base models where on-policy training plateaus, and reliable improvements with weak teachers.
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