Smyca-FOXM1 ribonucleoprotein complex promotes homologous recombination and tumor immune evasion to define a therapeutic target of triple-negative breast cancer

We previously identified that the long noncoding RNA Smyca is highly expressed in TNBC to elicit multiple pro-tumor effects. Here, we show that Smyca is induced by DNA damage to enhance homologous recombination (HR) repair.

Mechanistically, Smyca binds and guides FOXM1 to the promoters of a set of HR and nucleotide metabolism genes, thereby promoting their expression. Consequently, Smyca ablation induces BRCAness in HR-proficient TNBC, thereby sensitizing these tumors to platinum and PARP1 inhibitor (PARPi). Targeting Smyca/FOXM1 axis in combined with platinum or PARPi further activates cGAS/STING pathway and tumor immunogenicity to enhance anti-tumor immune surveillance.