Chromatin regulators play a broad role in regulating gene expression, and when gone awry, can lead to cancer. Here we demonstrate that ablation of the histone demethylase LSD1 in cancer cells increases repetitive element expression, including ERVs, and decreases expression of RNA-induced silencing complex (RISC) components. Significantly, this leads to dsRNA stress and activation of type 1 interferon, which stimulates anti-tumor T cell immunity and restrains tumor growth. Furthermore, LSD1 depletion enhances tumor immunogenicity and T cell infiltration in poorly immunogenic tumors, and elicits significant responses of checkpoint blockade-refractory mouse melanoma to anti-PD-1 therapy. Consistently, TCGA data analysis shows an inverse correlation between LSD1 expression and CD8+ T cell infiltration in various human cancers. Our study identifies LSD1 as a potent inhibitor of anti-tumor immunity and responsiveness to immunotherapy, and suggests LSD1 inhibition combined with PD-(L)1 blockade as a novel cancer treatment strategy. Overall design: Gene expression profiling of in vitro control and LSD1 KD MCF-7 cells (in biological replicates), as well as ex vivo scramble, LSD1 KO and LSD1/MDA5 DKO B16 tumor cells (in biological triplicates) was analyzed by RNA-seq. Genomic occupancy of LSD1, H3K4me1 and H3K4me2 in in vitro control and LSD1 KD MCF-7 cells, as well as ex vivo scramble and LSD1 KO B16 tumor cells was analyzed by ChIP-seq.