A single tumor contains a heterogeneous population of cancer cells. Some cancer cells express antigens and are susceptible to specific CTLs. However, other cancer cells are antigen-loss variants (ALVs) that escape these CTLs because they express little or no antigen. Here, we show that antigen-specific T cells can eliminate ALVs when the parental population expresses a model gp33 antigen (KAVYNFATM) at a level sufficient to be locally cross-presented by the nonmalignant stromal cells. That is, the ALVs are eliminated as bystanders because the stroma is destroyed. ALVs escape bystander killing when the bone marrow-derived and/or non-bone marrow-derived stroma does not express the appropriate MHC or when the amount of antigen is too low for effective cross-presentation. The rapid destruction of the stroma, including bone marrow-derived as well as sessile components, and of the parental cancer cells, may be essential for the complete rejection of established tumors by preventing variant escape.