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Non-small cell lung cancer (NSCLC) remains a leading cause of cancer-related mortality, and while immune checkpoint inhibitor (ICI) has transformed treatment, resistance remains a critical challenge. Beyond the T-cell-centric view, tumor-infiltrating B lymphocytes (TIL-Bs) and tertiary lymphoid structures (TLSs) have emerged as pivotal prognostic determinants; however, the mechanistic interplay within the B-cell-autoantibody axis remains underexplored. Unlike previous reviews that primarily catalogue B-cell abundance, this synthesis integrates emerging evidence from single-cell RNA sequencing (scRNA-seq) and spatial transcriptomics to dissect the spatiotemporal dynamics of B-cell subsets. We elucidate how the maturation status of TLSs dictates the functional plasticity of TIL-Bs, switching between anti-tumor effector phenotypes (e.g., antibody-secreting plasma cells) and pro-tumor regulatory roles (e.g., IL-10⁺ regulatory B cells). Furthermore, we systematically examine the dualistic role of autoantibodies-not merely as serological biomarkers but as active regulators of the tumor immune microenvironment (TIME) through complement activation and antibody-dependent cell-mediated cytotoxicity (ADCC). Finally, we highlight the clinical and translational implications of targeting this axis, proposing precision strategies such as B-cell-based vaccines and the modulation of TLS neogenesis to overcome ICIs resistance. This review provides a comprehensive roadmap for integrating B-cell biology into next-generation personalized immunotherapy for NSCLC.