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A Taxonomy of Architecture Options for Foundation Model-based Agents: Analysis and Decision Model
Bit-Flip Attacks on Vision-Language-Action Models: Action-Decoding Architecture Shapes the Vulnerability
A programmed cell death learning signature predicts immunotherapy response and identifies AP1S1 as a regulator of immune exclusion in breast cancer
Chin J Cancer Res. 2026 Aug 30;38(4):480-500. doi: 10.21147/j.issn.1000-9604.2026.04.08.
ABSTRACT
OBJECTIVE: Breast cancer remains a leading cause of global cancer mortality, characterized by profound heterogeneity. While immune checkpoint blockade (ICB) has transformed oncology, its efficacy in breast cancer is often hindered by "immune-cold" microenvironments and immune exclusion. Programmed cell death (PCD) is a critical regulator of tumor immune microenvironment (TIME). However, its role in the breast cancer immune microenvironment remains poorly understood.
METHODS: We integrated multi-omics data from six breast cancer cohorts (N=3,764) to develop a programmed cell death learning signature (PCDsig) using over 100 machine learning combinations. The model was benchmarked against 29 published signatures. Single-cell transcriptomic analysis decoded the immune landscape and cellular crosstalk. The role of adaptor-related protein complex 1 subunit sigma 1 (AP1S1) was validated through a clinical cohort, in vitro functional assays, and in vivo syngeneic mouse models.
RESULTS: PCDsig significantly stratified patient prognosis across all cohorts, consistently outperforming 29 existing models. High PCDsig scores correlated with immune-excluded phenotypes, reduced CD8+ T cell infiltration, and lower immunophenoscores. Single-cell analysis revealed that high-PCDsig tumors utilize vascular endothelial growth factor A (VEGFA) signaling to foster an immunosuppressive microenvironment. AP1S1 was identified as the core driver of immune exclusion. And our clinical cohort supported the immune exclusion effect of AP1S1. AP1S1 knockdown impaired tumor progression in vitro and fundamentally remodeled the tumor immune ecosystem in vivo. Combining AP1S1 inhibition with anti-programmed cell death ligand 1 (anti-PD-L1) therapy exerted profound synergistic effects, driven by massive infiltration and functional activation of cytotoxic Granzyme B (GZMB)+CD8+ T cells.
CONCLUSIONS: Our study establishes the PCDsig we developed is a potential prognostic and predictive biomarker for breast cancer. We provide the first evidence of AP1S1 as a core immunomodulatory oncogene that mediates immune exclusion. Targeting AP1S1 represents a highly promising strategy to sensitize cold breast tumors to ICB, offering a new perspective for precision immunotherapy.
PMID:42712842 | PMC:PMC13551362 | DOI:10.21147/j.issn.1000-9604.2026.04.08
A programmed cell death learning signature predicts immunotherapy response and identifies AP1S1 as a regulator of immune exclusion in breast cancer
Chin J Cancer Res. 2026 Aug 30;38(4):480-500. doi: 10.21147/j.issn.1000-9604.2026.04.08.
ABSTRACT
OBJECTIVE: Breast cancer remains a leading cause of global cancer mortality, characterized by profound heterogeneity. While immune checkpoint blockade (ICB) has transformed oncology, its efficacy in breast cancer is often hindered by "immune-cold" microenvironments and immune exclusion. Programmed cell death (PCD) is a critical regulator of tumor immune microenvironment (TIME). However, its role in the breast cancer immune microenvironment remains poorly understood.
METHODS: We integrated multi-omics data from six breast cancer cohorts (N=3,764) to develop a programmed cell death learning signature (PCDsig) using over 100 machine learning combinations. The model was benchmarked against 29 published signatures. Single-cell transcriptomic analysis decoded the immune landscape and cellular crosstalk. The role of adaptor-related protein complex 1 subunit sigma 1 (AP1S1) was validated through a clinical cohort, in vitro functional assays, and in vivo syngeneic mouse models.
RESULTS: PCDsig significantly stratified patient prognosis across all cohorts, consistently outperforming 29 existing models. High PCDsig scores correlated with immune-excluded phenotypes, reduced CD8+ T cell infiltration, and lower immunophenoscores. Single-cell analysis revealed that high-PCDsig tumors utilize vascular endothelial growth factor A (VEGFA) signaling to foster an immunosuppressive microenvironment. AP1S1 was identified as the core driver of immune exclusion. And our clinical cohort supported the immune exclusion effect of AP1S1. AP1S1 knockdown impaired tumor progression in vitro and fundamentally remodeled the tumor immune ecosystem in vivo. Combining AP1S1 inhibition with anti-programmed cell death ligand 1 (anti-PD-L1) therapy exerted profound synergistic effects, driven by massive infiltration and functional activation of cytotoxic Granzyme B (GZMB)+CD8+ T cells.
CONCLUSIONS: Our study establishes the PCDsig we developed is a potential prognostic and predictive biomarker for breast cancer. We provide the first evidence of AP1S1 as a core immunomodulatory oncogene that mediates immune exclusion. Targeting AP1S1 represents a highly promising strategy to sensitize cold breast tumors to ICB, offering a new perspective for precision immunotherapy.
PMID:42712842 | PMC:PMC13551362 | DOI:10.21147/j.issn.1000-9604.2026.04.08
An operational perturbation proteomics-based virtual cell model
Nature, Published online: 09 September 2026; doi:10.1038/s41586-026-11001-9
Temporal protein-abundance measurements from systematically perturbed breast cancer cell lines were generated to develop ProteinTalks, a virtual cell model that functions as an operational tool for diverse drug discovery tasks.Integration of proteomic aging clocks in a phase 2a clinical trial supports simultaneous geroprotective assessment
Nature Biotechnology, Published online: 07 September 2026; doi:10.1038/s41587-026-03286-y
Six proteomic clocks are applied in a clinical trial to assess anti-aging effects.MemForest: An Efficient Agent Memory System with Hierarchical Temporal Indexing
HiGraph: A Large-Scale Hierarchical Graph Dataset for Malware Analysis
$M^3-Verse$: A "Spot the Difference" Challenge for Large Multimodal Models
Can China’s Great Green Wall shape efforts to keep the world’s deserts at bay?
Nature, Published online: 15 April 2026; doi:10.1038/d41586-026-01102-w
Grand anti-desertification schemes often fail when trees die and funding dries up — yet one project has broken the mould.MAVEN: A Mesh-Aware Volumetric Encoding Network for Simulating 3D Flexible Deformation
Cardinality Estimation for High Dimensional Similarity Queries with Adaptive Bucket Probing
FAST-CAD: A Fairness-Aware Framework for Non-Contact Stroke Diagnosis
HoloTrauma 3X Triadic AI Co reasoning for robot assisted emergency maxillofacial reconstruction
npj Digital Medicine, Published online: 04 April 2026; doi:10.1038/s41746-026-02573-x
HoloTrauma 3X Triadic AI Co reasoning for robot assisted emergency maxillofacial reconstructionNot All Tokens See Equally: Perception-Grounded Policy Optimization for Large Vision-Language Models
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