FOS+ B cells: Key mediators of immunotherapy resistance in diverse cancer types

While immunotherapy has marked significant advances in cancer treatment, resistance remains a challenge. The complexity of the tumor microenvironment, particularly the role of B cell subpopulations, is a critical factor affecting treatment efficacy. In this study, we conducted analyses of single-cell RNA sequencing data from immunotherapy patients (<i>n</i> = 25) to explore the biomarker of immunotherapy resistance. Spatial transcriptome analysis, immunofluorescence analysis, and multi-cancer immunotherapy transcriptome analysis (<i>n</i> = 1,253) were used to validate our finding, and the potential mechanisms were explored. FOS⁺ B cells, identified across multiple cancer types, were associated with poor response to immunotherapy. FOS may form AP-1 (activator protein 1) with JUNB, thereby promoting the expression of Blimp-1 and subsequently facilitating the differentiation of B cells into immunosuppressive plasma cells. Furthermore, FOS⁺ B cells were linked to altered tumor necrosis factor signaling pathways, suggesting a mechanism for their immunosuppressive effects. Our findings highlight FOS⁺ B cells as important players in immunotherapy resistance, providing a novel biomarker for predicting treatment response. This study not only deepens our understanding of the immunological landscape influencing immunotherapy efficacy but also opens avenues for targeted interventions to overcome resistance.