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Robust transcriptomic hallmarks targeting intratumor heterogeneity in intrahepatic cholangiocarcinoma

Cell Rep Med. 2026 Mar 30:102708. doi: 10.1016/j.xcrm.2026.102708. Online ahead of print.

ABSTRACT

Intratumor heterogeneity (ITH) undermines transcriptome-based stratification in intrahepatic cholangiocarcinoma (iCCA). Here, we integrate multi-omics data from multi-region, single-region, and single-cell RNA sequencing cohorts to systematically characterize gene expression ITH. We uncover that immune and stromal heterogeneity are primary drivers of ITH, leading to misclassification of a median 27.8% of tumors by existing subtyping systems. To overcome this, we identify a low-intratumor-heterogeneity/high-intertumor-variability (LIHV) gene set and develop an ITH-insensitive classification system defining five subgroups: inflammatory (SI), metabolic (SII), atypical (SIII-1), immune-silent (SIII-2), and neurodegenerative (SIII-3). These subgroups exhibit distinct clinical outcomes, molecular features, immune landscapes, and therapeutic vulnerabilities. GPRC5A and VTCN1 serve as robust immunohistochemical biomarkers for SI and SIII tumors, while serum CEA and CA19-9 identify inflammatory iCCA. Therapeutically, HSP90 inhibition synergizes with anti-PD1 in inflammatory iCCA, whereas combined anti-PD1 and anti-TIM3 suppresses neurodegenerative iCCA. Collectively, our study provides a robust molecular framework and actionable therapeutic strategies for iCCA.

PMID:41916296 | DOI:10.1016/j.xcrm.2026.102708

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Chart Deep Research in LVLMs via Parallel Relative Policy Optimization

arXiv:2603.06677v1 Announce Type: cross Abstract: With the rapid advancement of data science, charts have evolved from simple numerical presentation tools to essential instruments for insight discovery and decision-making support. However, current chart data intelligence exhibits significant limitations in deep research capabilities, with existing methods predominantly addressing shallow tasks such as visual recognition or factual question-answering, rather than the complex reasoning and high-level data analysis that deep research requires. This limitation stems from two primary technical bottlenecks: at the training level, existing post-training techniques exhibit deficiencies in handling multi-dimensional reward signal interference and heterogeneous data gradient conflicts, preventing models from achieving balanced development across multiple capability dimensions; at the evaluation level, current methods remain limited to factual retrieval and basic computation, failing to assess end-to-end analytic reasoning and other deep research capabilities. To address the training challenge, we propose PRPO, which performs parallel optimization across reward dimensions and capability partitioning across data types, effectively disentangling conflicts between heterogeneous data and multi-dimensional reward signals while ensuring optimization stability. For the evaluation challenge, we construct MCDR-Bench based on the ``error uniqueness principle," transforming subjective generation assessment into objective error identification through controllable error injection, enabling quantifiable evaluation of deep research capabilities. Experimental validation confirms that the proposed PRPO and MCDR-Bench jointly establish a unified framework that systematically advances chart deep research through enhanced collaborative training and objective evaluation.
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