By integrating molecular network disruption analysis, single-cell sequencing technology, proteomics analysis, and functional validation experiments, we unveil a novel immunopathological process in sepsis, in which the infection-induced upregulation of serum matrix metalloproteinase-9 (MMP9) triggers CD4+ T cell exhaustion through 2 complementary pathways (T cell receptor [TCR] signal inhibition and calcium homeostasis disruption), and confirm the significant therapeutic effect of targeting MMP9 in restoring T cell function. This evidence concerns the gene MMP9 and Sepsis.