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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
A monocyte-centered framework for predicting immunochemotherapy efficacy in lung squamous cell carcinoma patients
EMBO Mol Med. 2026 Mar 30. doi: 10.1038/s44321-026-00410-y. Online ahead of print.
ABSTRACT
Lung cancer is the leading cause of cancer-related mortality worldwide, with lung squamous cell carcinoma (LUSC) comprising 20-30% of cases. Immunochemotherapy (IC) is the standard first-line treatment for advanced LUSC, yet reliable predictors of therapeutic response remain unavailable. Using single-cell multi-omics profiling of paired pre- and post-treatment tumor and blood samples, we observed that patients responding to IC exhibited significantly higher baseline levels of peripheral blood monocytes, tumor-infiltrating classical monocytes, and APOBEC3A+ monocytes across both compartments compared with non-responders. These associations were independently validated in additional cohorts using routine complete blood count testing and multiplex immunofluorescence analysis of native tumor tissues. Our findings reveal monocyte-related parameters as clinically accessible indicators that link systemic immunity with the tumor microenvironment and hold promise for predicting IC responsiveness in patients with LUSC.
PMID:41912871 | DOI:10.1038/s44321-026-00410-y
A monocyte-centered framework for predicting immunochemotherapy efficacy in lung squamous cell carcinoma patients
EMBO Mol Med. 2026 Mar 30. doi: 10.1038/s44321-026-00410-y. Online ahead of print.
ABSTRACT
Lung cancer is the leading cause of cancer-related mortality worldwide, with lung squamous cell carcinoma (LUSC) comprising 20-30% of cases. Immunochemotherapy (IC) is the standard first-line treatment for advanced LUSC, yet reliable predictors of therapeutic response remain unavailable. Using single-cell multi-omics profiling of paired pre- and post-treatment tumor and blood samples, we observed that patients responding to IC exhibited significantly higher baseline levels of peripheral blood monocytes, tumor-infiltrating classical monocytes, and APOBEC3A+ monocytes across both compartments compared with non-responders. These associations were independently validated in additional cohorts using routine complete blood count testing and multiplex immunofluorescence analysis of native tumor tissues. Our findings reveal monocyte-related parameters as clinically accessible indicators that link systemic immunity with the tumor microenvironment and hold promise for predicting IC responsiveness in patients with LUSC.
PMID:41912871 | DOI:10.1038/s44321-026-00410-y
Tumor-informed liquid biopsy detection of structural variants in high grade serous ovarian cancer
Oncoscience. 2026 Mar 5;13:44-54. doi: 10.18632/oncoscience.645. eCollection 2026.
ABSTRACT
BACKGROUND: High grade serous ovarian cancer (HGSOC) recurs frequently and commercial tests have emerged for tumor-informed, cell-free DNA (cfDNA)-based detection of minimal residual disease. These tests are based on somatic single nucleotide variants prevalent in many cancers and thus are not well matched to HGSOC, which is dominated by structural genomic rearrangements. The purpose of this study was to evaluate the feasibility of a structural-variant (SV)-informed, cfDNA-based method for detecting clonal and subclonal HGSOC disease burden.
METHODS: A method was developed for detecting patient-specific SV breakpoints using digital droplet PCR (ddPCR) with custom tumor-informed primer/probe pairs. Test parameters were first estimated using synthetic cfDNA generated by ultrasonication of genomic DNA from ovarian cancer cell lines. The optimized workflow was implemented in which whole genome sequencing of multisite pre-treatment HGSOC biopsies performed and high confidence SVs were called by multiple published SV callers. Real-time PCR and ddPCR were used for assay development.
RESULTS: Following the optimized workflow, tumor-specific SV breakpoint-spanning primers/probe sets of four HGSOC patients' multisite biopsies were designed and validated by real-time PCR and ddPCR. Together with four HGSOCs, a total of 29 SVs breakpoints-spanning tumor-informed primers/probe sets were designed and validated in multisite biopsies. 15 validated tumor-specific SVs were selected for quantification in their corresponding liquid biopsies using the validated ddPCR, and 9 had measurements in liquid biopsies.
CONCLUSIONS: Our result shows the detection of SVs from pre-treatment cfDNA using tumor-informed breakpoints-spanning ddPCR is feasible and may enable a novel and sensitive method for monitoring on-treatment disease burden.
PMID:41835357 | PMC:PMC12981705 | DOI:10.18632/oncoscience.645
SOX4 induces cisplatin resistance in cervical cancer cells by inhibiting aerobic glycolysis
Cell Death Discovery, Published online: 14 March 2026; doi:10.1038/s41420-026-02954-x
SOX4 induces cisplatin resistance in cervical cancer cells by inhibiting aerobic glycolysis