Gene

Cell biology

Biology

Virology

Apoptosis

Autophagy

Bystander effect

Immunology

Genetics

Mitochondrial DNA

Immune system

Abscopal effect

Chemistry

Immunotherapy

Nature Immunology

Autophagy supports both cellular and organismal homeostasis. However, whether autophagy should be inhibited or activated for cancer therapy remains unclear. Deletion of essential autophagy genes increased the sensitivity of mouse mammary carcinoma cells to radiation therapy in vitro and in vivo (in immunocompetent syngeneic hosts). Autophagy-deficient cells secreted increased amounts of type I interferon (IFN), which could be limited by CGAS or STING knockdown, mitochondrial DNA depletion or mitochondrial outer membrane permeabilization blockage via BCL2 overexpression or BAX deletion. In vivo, irradiated autophagy-incompetent mammary tumors elicited robust immunity, leading to improved control of distant nonirradiated lesions via systemic type I IFN signaling. Finally, a genetic signature of autophagy had negative prognostic value in patients with breast cancer, inversely correlating with mitochondrial abundance, type I IFN signaling and effector immunity. As clinically useful autophagy inhibitors are elusive, our findings suggest that mitochondrial outer membrane permeabilization may represent a valid target for boosting radiation therapy immunogenicity in patients with breast cancer. Autophagy controls cellular homeostasis and influences immune responses. Galluzzi and colleagues show that tumor cell autophagy opposes inflammatory cell death following radiation therapy and can be inhibited to enhance antitumor responses.

Mitochondrial DNA drives abscopal responses to radiation that are inhibited by autophagy