Biology subjects

Xun, Z.

Publications and source records attributed to Xun, Z..

4 recordsLinked to original sources

bioRxiv2026

CEACAM5/6+ Tumor Cells and IL-1β+ Macrophages Drive Resistance to Chemo-immunotherapy in Gastric Cancer

Chemo-immunotherapy is a first-line treatment for advanced gastric cancer, yet response rates remain limited and resistance mechanisms are poorly defined. Here we generate a single-cell atlas of 542,121 cells from 35 patients treated with anti-PD-1 plus chemotherapy, profiling pre- and post-treatment tumors linked to clinical response. Integrating spatial transcriptomics, immunohistochemistry, and bulk RNA sequencing, we identify two temporally distinct resistance programs. Intrinsic resistance in pre-treatment non-responders is marked by enrichment of CEACAM5/6 tumor cells that form immune-excluded spatial niches characterized by macrophage recruitment and CD8 T-cell exhaustion. Acquired resistance in post-treatment non-responders is driven by expansion of IL-1{beta} macrophages, which induces coordinated NF-{kappa}B activation across tumor and stromal compartments, promoting PD-L1 upregulation, epithelial-mesenchymal transition, and chronic inflammation. These findings delineate an evolutionary trajectory of resistance and nominate CEACAM5/6 and IL-1{beta} as predictive biomarkers and therapeutic targets to improve anti-PD-1-based combination strategies.

cancer biology↗

bioRxiv2026

Co-evolution of Oncogenic KRAS Signaling and LILRBhigh Macrophages Drives Pancreatic Cancer Recurrence

Pancreatic ductal adenocarcinoma (PDAC) frequently recurs after surgical resection, indicating that residual disease is sustained by coordinated tumor-microenvironment interactions. To define the biological basis of recurrence, we leverage large-scale clinical data from 2,710 patients, deeply characterized multi-omics profiling (whole-exome, bulk RNA, and single-nucleus sequencing) of 36 matched primary and locally recurrent PDACs, an in-house multiplex spatial imaging cohort of 190 patients, and extensive public datasets. Recurrent tumors were characterized by increased KRAS mutant allele dosage and reinforced KRAS signaling, accompanied by expansion of basal-like malignant cell states. In parallel, we identified an immunosuppressive macrophage population marked by high LILRB expression that spatially co-localized with KRAS-activated tumor cells. Functional studies showed that LILRB4+ macrophages enhanced tumor cell plasticity and progression, whereas inhibition of macrophage LILRB4 suppressed these phenotypes. Notably, a first-in-class human anti-LILRB4 antibody reduced macrophage-driven tumor traits, and dual targeting of KRAS signaling and LILRB4 achieved superior tumor control in macrophage-containing mouse models. These findings reveal a co-evolved tumor-immune niche underlying PDAC recurrence and nominate the KRAS-LILRB4 axis as a therapeutic vulnerability.

cancer biology↗

bioRxiv2026

NRF2 pathway activation and SPP1⁺TREM2⁺ macrophages drive chemoradiotherapy resistance in esophageal squamous cell carcinoma

Esophageal squamous cell carcinoma (ESCC) is among the most aggressive cancers, with low rates of durable response to chemoradiotherapy and limited therapeutic options for relapsed disease. To uncover mechanisms of treatment resistance and relapse, we performed comprehensive multi-omics profiling of >100 pre-treatment and post-relapse ESCC tumors from a prospective clinical trial (NCT04694391), integrating whole-exome/genome sequencing, bulk RNA-sequencing, single-cell RNA sequencing, and spatial transcriptomics. We identify somatic alterations in NFE2L2/KEAP1 in nearly 40% of relapsed patients, which are associated with upregulation of NRF2 signaling targets in resistant tumors and cell line models. At single-cell and spatial resolution, relapsed tumors are enriched for NRF2-activated epithelial cells that physically co-localize with immunosuppressive SPP1TREM2 macrophages. This co-localization suggests a synergistic interaction between NRF2-driven tumor programs and macrophage-mediated immune suppression that promotes relapse after chemoradiotherapy. Our findings nominate NFE2L2/KEAP1 mutations as predictive biomarkers for patient stratification and highlight therapeutic targeting of NRF2 signaling and SPP1TREM2 macrophages as rational strategies to overcome resistance in ESCC.

cancer biology↗

bioRxiv2024

Deep generative models generate mRNA sequences with enhanced translation capacity and stability

Despite the tremendous success of messenger RNA (mRNA) COVID-19 vaccines, the extension of this modality to a broader spectrum of diseases necessitates substantial enhancements, particularly in the design of mRNAs with elevated expression levels and extended durability. Here we present GEMORNA, a deep generative model designed to generate novel mRNA coding sequences (CDSs) and untranslated regions (UTRs) with superior translation capacity, comparable to the sophisticated task of language translation and free-form poetry composition with accurate grammar and semantics. Our AI model was trained on an extensive collection of RNA sequences from diverse families, further enhanced with labeled data to refine its performance. Remarkably, we demonstrate that our AI-generated mRNAs exhibited 8.2-fold and 15.9-fold increases in firefly luciferase expression compared to benchmark mRNAs in two different cell types. Additionally, Our AI- designed COVID-19 mRNA vaccine elicited a 4-fold increase in anti-COVID antibody titer in mice relative to BNT162b2. Furthermore, GEMORNAs versatility extends to circular mRNA design, which we facilitated a 27-fold increase in human erythropoietin protein expression in vivo than a systematically optimized benchmark sequence. We also created circular mRNAs with substantial improvements in expression levels, durability and anti-tumor cell cytotoxicity in mRNA-transduced CAR-T cells compared with an experimentally validated benchmark. In summary, GEMORNA generates novel mRNA sequences with significant performance improvements and has the potential to enable a wide range of therapeutic and vaccine applications.

synthetic biology↗