Reading view

Spatial transcriptomic-metabolic features of tumor foci and tumor capsule in microvascular invasion with hepatocellular carcinoma: A spatial multi-omics study

By: Zhi-Hui Luo · Na Wang · Jingwei Zhao · Fei Long · Si Wu · Wei Zhong · Wei-Ming Chen · Bicheng Wang · Kun Wang · Yufeng Yuan · Jingjiao Zhou · Chunhui Yuan · Fubing Wang

15 May 2026 at 18:00

PLoS Med. 2026 May 15;23(5):e1004703. doi: 10.1371/journal.pmed.1004703. eCollection 2026 May.

ABSTRACT

BACKGROUND: Microvascular invasion (MVI) is closely related to the recurrence and metastasis of hepatocellular carcinoma (HCC), but the underlying cellular mechanism remains largely elusive. This study aims to elucidate the regional cellular discrepancy between MVI-positive (MVI+) and MVI-negative (MVI-) HCC by integrating Spatial transcriptomics (ST) and spatial metabolomics (SM).

METHODS AND FINDINGS: ST and SM were performed on six tissue samples from four patients (including 2 MVI+, 2 MVI-, and 2 paratumor tissues), with the integration of 79 public single-cell RNA sequencing datasets of HCC. Patient identity was used as a covariate in the linear equation for regional differentially expressed gene analysis with the ST data. Clinical validation was conducted through multiplex immunofluorescence staining in 79 patients, together with external validation in the cancer genome atlas (TCGA)-liver hepatocellular carcinoma (LIHC) cohort (n = 299) and an independent microarray dataset (n = 62). For cell-type-specific metabolic profiling, spatial transcriptomic-metabolic registration was performed. The functional roles of key metabolites were further validated in vitro using inflammatory cancer-associated fibroblasts (iCAFs) derived from hepatic stellate cells (HSCs) and primary CAFs through co-culture models and various functional assays assessing cell proliferation, migration, and invasion. In the tumor lesion, a malignant STMN1+HMGN2+GPC3+ cell subtype enriched in MVI+ HCC was identified, which exhibited enhanced proliferative activity and was associated with poor prognosis. This finding was further confirmed in a local cohort of 79 patients, where multiplex immunofluorescence staining for the three genes (STMN1, HMGN2, and GPC3) showed significantly higher expression in the MVI+ group than in the MVI- group (p = 0.046). Integrated SM analysis further revealed that this cell population underwent metabolic reprogramming characterized by suppressed glycerolipid metabolism. In the tumor capsule, iCAFs-related genes were downregulated in MVI+ cases, and iCAFs were located distally from the tumor boundary. Spatial metabolite mapping showed a strong correlation between taurine and iCAFs, and functional assays demonstrated that taurine promotes HCC proliferation and migration by suppressing iCAF activity. One limitation of this study is the small sample size of spatial omics data, which hinders a more complete molecular functional analysis of the STMN1+HMGN2+GPC3+ cell subtype and iCAFs in MVI+ HCC. Larger-scale ST cohorts are required to further validate and expand the findings of this study.

CONCLUSIONS: This integrative spatial atlas proposes a hypothesis that there exists a highly proliferative and metabolically reprogrammed malignant cell subtype in the tumor lesion of MVI+ HCC, and that taurine in the tumor capsule modulates iCAF activity to influence tumor progression. The exploratory results provide mechanistic insights into MVI-related HCC progression and offer potential avenues for targeted therapeutic intervention of MVI+ HCC.

PMID:42139279 | PMC:PMC13178920 | DOI:10.1371/journal.pmed.1004703

I-CALM: Incentivizing Confidence-Aware Abstention for LLM Hallucination Mitigation

cs.AI, q-bio.NC updates on arXiv.org

By: Haotian Zong · Binze Li · Yufei Long · Sinyin Chang · Jialong Wu · Gillian K. Hadfield

7 April 2026 at 12:00

arXiv:2604.03904v1 Announce Type: cross Abstract: Large language models (LLMs) frequently produce confident but incorrect answers, partly because common binary scoring conventions reward answering over honestly expressing uncertainty. We study whether prompt-only interventions -- explicitly announcing reward schemes for answer-versus-abstain decisions plus humility-oriented normative principles -- can reduce hallucination risk without modifying the model. Our focus is epistemic abstention on factual questions with a verifiable answer, where current LLMs often fail to abstain despite being uncertain about their answers. We first assess self-reported verbal confidence as a usable uncertainty signal, showing stability under prompt paraphrasing and reasonable calibration against a token-probability baseline. We then study I-CALM, a prompt-based framework that (i) elicits verbal confidence, (ii) partially rewards abstention through explicit reward schemes, and (iii) adds lightweight normative principles emphasizing truthfulness, humility, and responsibility. Using GPT-5 mini on PopQA as the main setting, we find that confidence-eliciting, abstention-rewarding prompts, especially with norms, reduce the false-answer rate on answered cases mainly by identifying and shifting error-prone cases to abstention and re-calibrating their confidence. This trades coverage for reliability while leaving forced-answer performance largely unchanged. Varying the abstention reward yields a clear abstention-hallucination frontier. Overall, results show the framework can improve selective answering on factual questions without retraining, with the magnitude of effect varying across models and datasets. Code is available at the following https://github.com/binzeli/hallucinationControl.