PCAT6 Regulates IGF2BP1/PD-L1 to Promote Immune Escape in Breast Cancer

This study aims to elucidate the mechanism through which prostate cancer-associated transcript 6 (PCAT6) modulates immune escape in triple-negative breast cancer (TNBC), focusing on its interaction with IGF2BP1 and PD-L1.

We analyzed 68 paired TNBC clinical specimens and utilized TNBC cells (BT-549, MDA-MB-468) with lentivirus-mediated gene manipulation. Functional assays included cell counting kit-8, EdU incorporation, Transwell migration/invasion, and co-culture with activated CD8⁺ T cells. Immune function was assessed through LDH release, ELISA (IFN-γ and granzyme B), and flow cytometry. Molecular interactions were investigated via RNA immunoprecipitation, RNA pulldown, fluorescence in situ hybridization, and actinomycin D-based mRNA stability assays.

PCAT6 was markedly upregulated in TNBC tissues and cell lines, correlating with advanced tumor stage and lymph node metastasis. PCAT6 knockdown restrained tumor cell proliferation, migration, and invasion while downregulating PD-L1 expression. In co-culture systems, PCAT6 depletion enhanced CD8⁺ T cell cytotoxicity, evidenced by increased inflammatory factor secretion and elevated IFN-γ⁺ CD8⁺ T cell proportion. Mechanistically, PCAT6 interacted with IGF2BP1 in the cytoplasm and promoted IGF2BP1-mediated stabilization of PD-L1 mRNA. Rescue experiments confirmed that PCAT6 required IGF2BP1 to sustain PD-L1 expression and mRNA stability.

PCAT6 facilitates TNBC immune escape by enhancing PD-L1 mRNA stability through IGF2BP1, identifying the PCAT6/IGF2BP1/PD-L1 axis as a potential therapeutic target for breast cancer immunotherapy.