Decoding Paraneoplastic Neuromyelitis Optica: A Multi-Omics Investigation of Tumor-Driven T and B Cell Dynamics

Wenjing Huang¹Ruyu Lin²Xianyi Zeng³Hai Wang^4*Jichun Yan^5*

• ¹The First People's Hospital of Qinzhou, Qinzhou, China
• ²Clinical Medicine, Fujian Medical University, Fujian, China
• ³China Unicom Digital Intelligence Medical Technology Co., Ltd., Guangzhou, China
• ⁴Rheumatology and Immunology Department，Yue Bei People's Hospital, Shaoguan, China
• ⁵Ganzhou People's Hospital, Ganzhou, China

A significant subset of Neuromyelitis Optica Spectrum Disorder (NMOSD) cases occurs as a paraneoplastic syndrome, where an underlying tumor triggers a devastating autoimmune attack against the central nervous system. This autoimmune response is driven by pathogenic aquaporin-4 autoantibodies (AQP4-IgG), likely initiated by the tumor's expression of AQP4 in a phenomenon of molecular mimicry. Understanding the precise immune mechanisms that link a patient's cancer to their neurological disease is critical for early diagnosis of the occult malignancy and for improved patient outcomes. This review explores how multi-omics technologies are revolutionizing the investigation of T and B cell functional dynamics in this specific context, offering unprecedented resolution into the pathogenesis of paraneoplastic NMOSD. The application of integrated multi-omics -including genomics, epigenomics, transcriptomics (particularly single-cell RNA-seq), proteomics, and metabolomics-provides a holistic framework to dissect the specific immune response directed against both the tumor and the CNS. Transcriptomics, notably scRNA-seq, can deconstruct the heterogeneity of tumor-infiltrating and circulating T and B cells to identify the pathogenic subsets responsible for the autoimmune pathology. Proteomics can aid in identifying tumor-specific biomarkers, while metabolomics offers insights into the metabolic vulnerabilities of the autoreactive immune cells. Multi-omics analyses reveal the cellular and molecular cascade of the paraneoplastic response. High-throughput T-cell receptor (TCR) and B-cell receptor (BCR) sequencing provides direct evidence of oligoclonal expansions, identifying the specific T and B cell clones that likely recognize shared AQP4 epitopes on both the cancer cells and CNS astrocytes. These expanded B cells show hallmarks of a mature, antigen-driven response, including classswitching and affinity maturation of the pathogenic AQP4-IgG. Furthermore, analyses of T cell dynamics reveal a pro-inflammatory environment, with functional impairment of regulatory T cells (Tregs) and a skewed balance towards Th17 and Th1 cells, which is likely initiated by the tumor and perpetuated in the CNS via critical T-B cell interactions, such as the IFN-I → B-cell → IL-6 → pathogenic Th17 axis. Despite these insights, substantial challenges remain in translating these findings into clinical practice. A key hurdle is using multi-omics to develop a reliable molecular signature that can # CORRESPONDENCE：Wang Hai，