Triple-negative breast cancer (TNBC) is a difficulty and bottleneck in the clinical treatment of breast cancer due to a lack of effective therapeutic targets. Herein, we first report that secernin 2 (SCRN2), an uncharacterized gene in human cancer, acts as a novel tumor suppressor in TNBC to inhibit cancer progression and enhance therapeutic sensitivity to poly(ADP-ribose) polymerase (PARP) inhibition both in vitro and in vivo. SCRN2 is downregulated in TNBC through chaperone-mediated autophagic degradation, and its downregulation is associated with poor patient prognosis. Moreover, SCRN2 impedes the proteasomal degradation of histone-lysine N-methyltransferase 2C (KMT2C) by recruiting Bcl2-associated athanogene 2 to block the interaction of KMT2C with E3 ubiquitin-protein ligase CHIP. Consistently, SCRN2 transcriptionally activates Bcl2-modifying factor by amplifying histone H3 monomethylation at lysine 4 at its enhancer, thereby inducing intrinsic apoptosis. Notably, KMT2C knockdown restores the impaired TNBC progression caused by SCRN2 overexpression both in vitro and in vivo. Furthermore, SCRN2 decreases the expression of key DNA repair-related genes and induces endogenous DNA damage, thus conferring therapeutic sensitivity of TNBC cells to PARP inhibition. Collectively, these findings identify SCRN2 as a novel suppressor of TNBC, reveal its mechanism of action, and highlight its potential role in TNBC therapy.