Cancers frequently evade cytotoxic T lymphocyte–mediated destruction through loss or down-regulation of tumor antigens and antigen-presenting major histocompatibility complex molecules. Therefore, we have concentrated our efforts on immunological strategies that destroy nonmalignant stromal cells essential for the survival and growth of cancer cells. In this study, we developed a non–T cell receptor transgenic, immunocompetent tumor model to determine whether tumor-bearing hosts’ own immune systems could eliminate cancer cells through stromal targeting and what role CD4⁺ T cells play alongside CD8⁺ T cells in this process. We found that aggressive cancers could be eradicated by T cell targeting of tumor stroma. However, successful elimination required the cooperation of CD4⁺ and CD8⁺ T cells not only during the induction phase but also during the effector phase in the tumor microenvironment, implying a new role for CD4⁺ T cells that has not been previously described. Our study demonstrates the potential of stromal targeting as a cancer immunotherapy and suggests that successful anticancer strategies must facilitate cooperation between CD4⁺ and CD8⁺ T cells at the right times and the right places.