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Cytotoxic T lymphocytes (CTLs) play a key role in antitumor immunity, and the function of these cells can be suppressed in the tumor microenvironment (TME). Lu et al. show how epigenetic states in the TME suppress effector functions and can be countered by small molecule–targeted therapy in colon cancer. CTLs infiltrate tumors and have high expression of the histone methyltransferase SUV39H1, which decorates the histone H3K9me3. H3K9me3 is enriched in the promoter region of several key CTL effector genes and suppressed their expression. By specifically targeting SUV39H1 with a small-molecule inhibitor, called F5446, expression of the effector genes is enhanced, and the antitumor function of CTLs in the tumor microenvironment is increased. Read more in this issue on page 414. Original image from Fig. 1. Artwork by Lewis Long.