DNA repair

DNA damage

Genome instability

Immunotherapy

Biology

Gene

Cancer

Chromosome instability

Immunology

Immune checkpoint

Signal transduction

Cell biology

Chromosome

Epigenetics

Cancer research

Genetics

DNA re-replication

Immune system

Eukaryotic DNA replication

Biochimica et Biophysica Acta (BBA) - Reviews on Cancer

Genomic and chromosomal instability are hallmarks of cancer and shape the genomic composition of cancer cells, thereby determining their behavior and response to treatment. Various genetic and epigenetic alterations in cancer have been linked to genomic instability, including DNA repair defects, oncogene-induced replication stress, and spindle assembly checkpoint malfunction. A consequence of genomic and chromosomal instability is the leakage of DNA from the nucleus into the cytoplasm, either directly or through the formation and subsequent rupture of micronuclei. Cytoplasmic DNA subsequently activates cytoplasmic DNA sensors, triggering downstream pathways, including a type I interferon response. This inflammatory signaling has pleiotropic effects, including enhanced anti-tumor immunity and potentially results in sensitization of cancer cells to immune checkpoint inhibitors. However, cancers frequently evolve mechanisms to avoid immune clearance, including suppression of inflammatory signaling. In this review, we summarize inflammatory signaling pathways induced by various sources of genomic instability, adaptation mechanisms that suppress inflammatory signaling, and implications for cancer immunotherapy.

Genomic instability, inflammatory signaling and response to cancer immunotherapy