Cancer Immunotherapy: Targeting TREX1 Has the Potential to Unleash the Host Immunity against Cancer Cells

Chromosomal instability and DNA damage are hallmarks of cancers that can result in the accumulation of micronuclei, cytosolic chromatin fragments (CCFs), or cytosolic DNA species (cytoDNA). The cyclic GMP-AMP synthase (cGAS) is a DNA sensor that recognizes cytosolic DNA and chromatin fragments and subsequently triggers a systemic type I interferon response via the cGAS-STING pathway. Although cancer cells usually contain a high level of chromosomal instability, these cells can avoid the induction of the interferon (IFN) response either by silencing cGAS-STING or the upregulation of the three prime exonuclease 1 (TREX1). TREX1 restricts the spontaneous activation of the cGAS-STING pathway through the degradation of cytoDNA; this in turn limits tumor immunogenicity allowing cancer cells to evade immune detection. Deletion of TREX1 in different cancer types has been shown to decrease tumor growth and increase tumor immune infiltration in pre-clinical mice models. These recent studies also showed the efficacy of TREX1-targeting in combination with anti-PD-1 immune checkpoint blockade. Therefore, targeting TREX1 represents a unique therapeutic strategy to induce an amplified induction of a type I IFN response, promoting the host’s immune response against chromosomally unstable cancer cells. We here discuss these recent advances obtained in preclinical cancer models that pave the way to develop TREX1 inhibitors and to find new avenues to target the broad cGAS-STING pathway signaling in cancer therapy.