PRELID1 and VDAC3 Coordinate a Senescence-Like State in Germinal Center B Cells to Promote IL-7-Driven Antitumor...

Colorectal cancer (CRC) is characterized by an immune-suppressive microenvironment that facilitates to tumor progression and immunotherapy resistance. Emerging evidence indicates that tumor-infiltrating B cell subsets play dual roles in modulating antitumor immunity. However, the mechanisms underlying their regulatory functions remain poorly understood. In this study, we constructed single-cell transcriptomic analyses and a Bgc adoptive transfer model in B cell-deficient mice, performing multifaceted validation to confirm that targeting the PRELID1-VDAC3-IL-7 axis in senescence-like germinal center B cells enhances sensitivity to anti-PD-L1 immunotherapy. Mechanistically, we identify a senescence-like state in germinal center B cells (Bgc) that enhances antitumor immunity in CRC by promoting Interleukin-7 (IL-7) secretion and alleviating CD8⁺ T cell exhaustion. Specifically, this senescence-like state is driven by PRELID1 and VDAC3 through their cooperative regulation of mitochondria-lysosome interactions in Bgc cells, which enhances IL-7 secretion and promotes functional crosstalk with CD8⁺ T cells to sustain antitumor immunity. In summary, our findings support a combinatorial strategy integrating targeting of the PRELID1-VDAC3-IL-7 axis in senescence-like Bgc cells with anti-PD-L1 immunotherapy for colorectal cancer.