H3K9 methylation drives resistance to androgen receptor–antagonist therapy in prostate cancer

Significance This study reveals that antiandrogen therapy induces viral mimicry responses that are crucial for antitumor activity. H3K9 trimethylation to silence endogenous repeat elements is essential for regaining heterochromatin stability and progression to antiandrogen resistance in prostate cancer. We found that the H3K9 trimethylation machinery is linked to poor outcomes in men with prostate cancer. Blockade of this epigenetic axis can resensitize drug-resistant tumors and elicit cytotoxic interferon responses. Antiandrogen timing and regulation of the H3K9 methylation–endogenous repeat elements– interferon axis should be considered in the development of novel epigenetic therapies and immunotherapeutic strategies for prostate cancer.