Targeting the PRMT5-CBX8 axis overcomes dual barriers of CD8⁺ T cell exclusion and tumor stemness for sensitizing TNBC to anti-PD-1 therapy.

The efficacy of immune checkpoint blockade in triple-negative breast cancer (TNBC) is limited by poor CD8⁺ T cell infiltration. Here, we demonstrate that tumor-derived proprotein convertase subtilisin/kexin type 9 (PCSK9) drives CD8⁺ T cell exclusion, and we identify protein arginine methyltransferase 5 (PRMT5) as an important epigenetic regulator responsible for PCSK9 expression in TNBC. Mechanistically, we elucidate that PRMT5-mediated methylation of the chromobox homolog 8 (CBX8) facilitates its interaction with the deubiquitinase USP7, which removes K33-linked ubiquitination on CBX8. This post-translational modification modulates CBX8 function, enabling it to drive the transcriptional upregulation of key downstream targets PCSK9, which inhibits CD8+ T cell infiltration, and LGR5, which enhances tumor stemness. Crucially, inhibition of PRMT5 profoundly sensitizes TNBC tumors to anti-PD-1 therapy in vivo. Our work unveils a novel epigenetic pathway orchestrated by PRMT5 that converges on the functional modulation of CBX8 to synchronously governs CD8⁺ T cell exclusion and tumor stemness, nominating PRMT5 inhibition as a compelling therapeutic strategy for combination immunotherapy in TNBC.