GDF15 hijacks B cells to fuel the lifeblood of tumor salvage pyrimidine synthesis

ABSTRACT: B cell-tumor crosstalk has emerged as a critical determinant of tumor progression; however, its role in metabolic reprogramming and therapeutic resistance remains poorly understood. Here, we uncover a metabolic feedback loop that drives resistance to dihydroorotate dehydrogenase (DHODH) inhibitors. Mechanistically, DHODH inhibition induces lactylation of TERF2IP at lysine 208 (K208) in tumor cells, enabling TERF2IP to scaffold IKK and p65, thereby promoting p65 phosphorylation and subsequent GDF15 expression. Secreted GDF15 recruits B cells into the tumor microenvironment, where they activate JAK1-STAT3-IL-1beta signaling, which in turn enhances ERK-cMYC-UCK2-driven salvage pyrimidine synthesis and confers resistance to DHODH inhibition. Through high-throughput screening, we identify melitracen as a synergistic agent that reverses this B cell-dependent resistance. Collectively, our findings delineate a B cell-orchestrated regulatory axis governing tumor pyrimidine metabolism that underlies DHODH inhibitor resistance, and propose a clinically translatable combinatorial therapeutic strategy for cancer treatment.

INSTRUMENT(S): Liquid Chromatography MS - alternating - reverse-phase

PROVIDER: MTBLS15820 | MetaboLights | 2026-09-27

REPOSITORIES: MetaboLights