The　role　of　thymic　epithelial　cells　(TECs)　in　eliminating　self-reactive　T　cells　through　the　presentation　of　self-antigens　is　well-established.　However,　it　remains　unclear　whether　TECs　can　eliminate　tumor-reactive　CD8+　T　cells　by　presenting　tumor　antigens.　In　this　study,　we　observed　that　CD73+　Granzyme　B+　peripheral　activated　CD8+　T　cells　undergo　apoptosis　in　the　medullary　region　of　the　thymus　in　DEN-CCL4-induced　spontaneous　HCC　mice,　but　not　in　the　naïve　control　group.　Mechanistically,　HCC　cells　manipulate　the　thymus　to　recruit　peripheral　activated　CD8+　T　cells　through　the　CCL19/CCL21-CCR7　axis.　Additionally,　TECs　capture　antigens　from　HCC　cells　for　subsequent　antigen　presentation　instead　of　de　novo　expressing　tumor　antigens.　When　tumor-associated　CD8+　T　cells　homing　to　the　thymus　recognize　the　same　tumor　antigen　presented　by　TECs,　activation-induced　cell　death　(AICD)　is　initiated　in　these　T　cells.　Thymectomy　redistributes　CD8+　T　cells　into　the　tumor　focus　to　suppress　HCC　growth.　Alternatively,　both　inhibiting　CCL19/CCL21　expression　of　thymic　cells　using　an　AMPK　activator　and　blocking　CCR7　on　CD8+　T　cells　binding　with　ligands　using　Cmp2105　significantly　reduces　tumor-educated　thymus　dependent　immune　evasion.　Our　findings　collectively　demonstrate　that　HCC　manipulates　the　thymus　to　trigger　immune　escape;　pharmacologically　targeting　CCL19/CCL21-CCR7　axis　to　inhibit　thymus　homing　can　increase　CD8+　T　cells　in　the　tumor　microenvironment.　©　2025