Neuroendocrine carcinoma of the cervix (NECC) is a rare but highly aggressive subtype of cervical cancer characterized by rapid progression, early metastasis, and poor survival. Current treatment strategies are largely adapted from other neuroendocrine malignancies and conventional cervical cancers, yet clinical outcomes remain unsatisfactory. Although genomic studies have begun to uncover recurrent genetic alterations in NECC, the tumor immune microenvironment (TIME) and cellular interactions driving disease progression remain poorly understood, limiting the development of effective targeted therapies.

In a new study published in Genes & Diseases, researchers from Fudan University and Shanghai Key Laboratory of Female Reproductive Endocrine-Related Diseases utilized multi-omic profiling to characterize the cellular heterogeneity and immune evasion mechanisms driving NECC progression.

The investigators performed single-cell RNA sequencing (scRNA-seq) and T-cell receptor sequencing (TCR-Seq) on patient-derived surgical tissues, specifically comparing NECC with adenocarcinoma and squamous cell carcinoma controls. Following enzymatic tissue dissociation and acridine orange/propidium iodide staining evaluated on a Countstar Fluorescence Cell Analyzer, viable single cells were isolated for high-resolution transcriptomic profiling. This analysis mapped the distinct cellular compartments within the NECC microenvironment, focusing on neuronal progenitor cells (NPCs).

Trajectory and pseudotime analyses identified three distinct NPC states: early differentiated NPCs (edNPCs) that facilitate TME remodeling, transitional differentiated NPCs (tdNPCs) characterized by glycolytic metabolic reprogramming, and late differentiated NPCs (ldNPCs) exhibiting cell-cycle overactivation and rapid cellular proliferation. To define the active molecular pathways within these subpopulations, the team used single-cell gene set enrichment analysis (ssGSEA). Cellular communication profiling identified delta-like ligand 3 (DLL3) as a central signaling hub bridging malignant progression and local immunosuppression. Immunohistochemical validation confirmed that DLL3 is highly and specifically expressed in NECC specimens relative to cervical adenocarcinoma and squamous cell carcinoma tissues.

Mechanistically, DLL3-mediated crosstalk with surrounding tumor-infiltrating lymphocytes (TILs)—primarily via DLL3–NOTCH1 and DLL3–NOTCH2 pathways—promotes T-cell exhaustion and impairs cytotoxic immune responses. Furthermore, a CD38–PECAM1 signaling axis between plasma cells and T cells was shown to reinforce this local immunosuppressive network.
To validate these findings in a translational context, the researchers established a patient-derived NECC organoid and autologous TIL co-culture system. Treatment with the DLL3-targeted bispecific T-cell engager tarlatamab (AMG757) demonstrated anti-tumor activity by inducing T-cell activation, elevating the expression of perforin, CD137, and CD107a in CD8+ T cells, and decreasing organoid cell viability. In conclusion, this study defines the spatial and transcriptomic architecture of NECC, identifying the DLL3-NOTCH axis as a driver of immune evasion and a viable therapeutic target for precision oncology.

Reference

Title of Original Paper: DLL3 serves as a pivotal hub bridging malignant progression and immunosuppression in NECC with therapeutic implications validated via the organoid-TIL co-culture system

Journal: Genes & Diseases

Genes & Diseases is a journal for molecular and translational medicine. The journal primarily focuses on publishing investigations on the molecular bases and experimental therapeutics of human diseases. Publication formats include full length research article, review article, short communication, correspondence, perspectives, commentary, views on news, and research watch.

DOI: https://doi.org/10.1016/j.gendis.2025.101737

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Genes & Diseases publishes rigorously peer-reviewed and high quality original articles and authoritative reviews that focus on the molecular bases of human diseases. Emphasis is placed on hypothesis-driven, mechanistic studies relevant to pathogenesis and/or experimental therapeutics of human diseases. The journal has worldwide authorship, and a broad scope in basic and translational biomedical research of molecular biology, molecular genetics, and cell biology, including but not limited to cell proliferation and apoptosis, signal transduction, stem cell biology, developmental biology, gene regulation and epigenetics, cancer biology, immunity and infection, neuroscience, disease-specific animal models, gene and cell-based therapies, and regenerative medicine.

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