PRELID1 and VDAC3 Coordinate a Senescence‐Like State in Germinal Center B Cells to Promote IL‐7–Driven Antitumor Immunity in Colorectal Cancer

ABSTRACT 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.