PARPi treatment enhances radiotherapy-induced ferroptosis and antitumor immune responses via the cGAS signaling pathway in colorectal cancer

In cancer cells, poly (ADP-ribose) polymerase (PARP)-1 and PARP2 initiate and regulate DNA repair pathways to protect against DNA damage and cell death caused by radiotherapy or chemotherapy. Radiotherapy and PARP inhibitors (PARPis) have been combined in clinical trials, but their action mechanisms remain unclear. Here, we show that activated by ionizing radiation (IR) generated dsDNA, cyclic GMP-AMP synthase (cGAS) signaling promoted regulated cell death, specifically ferroptosis, via the activating transcription factor 3 (ATF3)-solute carrier family 7 member 11 axis and the antitumor immune response via the interferon-beta-CD8(+) T cell pathway. Niraparib, a widely used PARPi, augmented cGAS-mediated ferroptosis and immune activation. In colorectal cancer models, cGAS knockdown (KD) compromised IR-induced ferroptosis via downregulation of ATF3 (key ferroptosis regulator) expression. cGAS depletion reversed IR-induced infiltration of CD8(+ )T or CD8(+)GZMB(+) T cells in the cGAS KD group. Survival analysis of paired tumor samples before and after standard radiotherapy revealed that high expression levels of cGAS, ATF3, and PTGS2 and high density of CD8(+) T cells resulted in a significantly high disease-free survival rate in patients with rectal cancer. Therefore, PARPi treatment increases the cytoplasmic accumulation of dsDNA caused by IR, triggering the cGAS signaling-mediated tumor control in cancer cell lines and mouse xenograft models.

Automated summary

In cancer cells, the PARP-1 and PARP2 proteins regulate DNA repair pathways to protect against therapy-induced DNA damage and cell death. Combining PARP inhibitors (PARPis) with radiotherapy has been effective in clinical trials, but the mechanisms underlying their action are still unclear. This study reveals that the activation of cyclic GMP-AMP synthase (cGAS) signaling by ionizing radiation (IR)-induced DNA damage leads to regulated cell death, known as ferroptosis, and an anti-tumor immune response. Additionally, a widely used PARPi called niraparib enhances cGAS-mediated ferroptosis and immune activation. The depletion of cGAS expression compromises IR-induced ferroptosis and reverses the infiltration of CD8(+) T cells in colorectal cancer models. High expression of cGAS, ATF3, and PTGS2, as well as a high density of CD8(+) T cells, is associated with a significantly higher disease-free survival rate in patients with rectal cancer after standard radiotherapy.