show Abstracthide AbstractImmunotherapy is currently a prime approach to cancer treatment. Despite the promise of immunotherapies such as immune checkpoint blockade on multiple cancers, most patients do not have a response or become resistant to treatment. Recent work indicate that epigenetic therapies converge with cancer immunotherapy through 'viral mimicry', the antiviral response triggered by endogenous nuclei acids that derived from aberrantly transcribed endogenous retrotransposons. However, epigenetic factors that regulate endogenous retrotransposons and further modulate the immune sensitivity of tumor cells is largely unknown. Here we identified the histone demethylase PHD finger protein 8 (PHF8, KDM7B), a Jumonji C domain-containing protein that erases repressive histone marks as an essential mediator of immune escape. We found that depletion of PHF8 abrogates tumor growth, induces immune memory and augments sensitivity to immune checkpoint blockade in multiple tumor models without directly affecting tumor cell proliferation. Overall design: Comparative gene expression profiling analysis of RNA-seq data for CT26 control (n=8), Phf8 sh1 (n=8), and Phf8 sh2 (n=8) tumor tissues; PANC28 control (n=3) and sgPHF8 (n=3) cells; CT26 control (n=3), sgPhf8 (n=3) and sgPhf8+Phf8 (n=3) cells.