Background <p>Cervical cancer (CC) is a leading cause of cancer-related deaths in women, and understanding the tumor immune microenvironment is crucial for identifying novel biomarkers and therapeutic targets. While T cells have been extensively studied in oncology, the role of B cells in CC remains poorly understood.</p> Methods <p>In this study, we generated and integrated multi-omics data, including single-cell RNA sequencing, single-nucleus RNA sequencing, spatial transcriptomics, bulk RNA sequencing, and multiplex immunofluorescence to investigate the composition and transcriptomic states of B cells in CC.</p> Results <p>Initially, we analyzed plasma cells, classifying them into IgA⁺ and IgG⁺ subtypes. We found that the proportion of IgA⁺ plasma cells was lower in cancer samples, whereas IgG⁺ plasma cells were higher. IgA⁺ plasma cells exhibited protein folding and B cell activation characteristics, while IgG⁺ plasma cells were associated with apoptosis and immune suppression. Subsequently, we focused on two specific plasma cell populations, MANF_PC and HSPA1B_PC. MANF_PC, which were predominantly enriched in normal tissues, were linked to enhanced antibody synthesis and better prognosis, while HSPA1B_PC, primarily found in cancerous tissues, were associated with apoptotic pathways and poor clinical outcomes. Importantly, HSPA1B_PC are associated with tertiary lymphoid structures (TLS), where they show significant spatial colocalization with immunosuppressive T cell subsets, including Tregs and Th17 cells within TLS.</p> Conclusions <p>We identified distinct plasma cell subsets in CC and found that HSPA1B_PC are enriched in tumors, associated with immunosuppressive T cells in TLS. These findings suggest that HSPA1B_PC contribute to an immunosuppressive microenvironment in CC, highlighting their potential as therapeutic targets.</p>