BTLA, CD160, and LIGHT are differentially expressed on tumor-specific CD8⁺ T cells, and depending on their expression, they can mediate distinct outcomes: immune tolerance or effective immunity against tumor targets. Three potential interactions are shown. Left: If BTLA or CD160 is expressed and LIGHT expression is either low or absent, the coinhibitory BTLA-CD160-HVEM complex will be dominant, resulting in negative regulation of the tumor-specific CD8⁺ T cell by the human tumor. Middle: If LIGHT, BTLA, and CD160 are all expressed, they might form a complex with HVEM. This could trimerize HVEM, resulting in positive or negative regulation of the T cell by the tumor. Right: If LIGHT is expressed with little to no BTLA or CD160, the tumor-specific T cells receive a positive signal from the HVEM-expressing tumor, resulting in robust functional activation of the tumor-specific T cell. Thus, attenuation of BTLA via either CpG or antibody blockade might augment T cell–mediated immunotherapy for cancer. Potent tumor-specific T cell responses are mediated with conventional vaccination and CpG, which downregulates BLTA expression on T cells, as revealed by new findings reported by Derré et al. (9) and as represented in the right panel. Adapted with permission from Trends in immunology (22).