The association of autoimmunity with antitumor immunity challenges a paradigm of selective surveillance against tumors. Aided with well‐characterized models of robust autoimmunity, we show that self‐antigen‐specific effector T (Teff) cell clones could eradicate tumor cells. However, a tumor microenvironment reinforced by Treg cells and myeloid‐derived suppressor cells (MDSCs) presented a barrier to the autoimmune effectors, more so in tumors than in healthy tissues. This barrier required optimal CTLA4 expression in Teff cells. In a spontaneous model of breast cancer, subtle reductions in CTLA4 expression impeded tumor onset and progression, providing the first direct evidence that CTLA4 inhibits spontaneous tumor development. In an adoptive therapy model of lymphoma, self‐antigen‐specific Teff cells were potentiated by even a modest reduction of CTLA4. A subtle reduction of CTLA4 did not curtail Treg‐cell suppression. Thus, Teff cells had an exquisite sensitivity to physiological levels of CTLA4 variations. However, both Treg and Teff cells were impacted by anti‐CTLA4 antibody blockade. Therefore, whether CTLA4 impacts through Treg cells or Teff cells depends on its expression level. Overall, the results suggest that the tumor microenvironment represents an “immunoprivileged self” that could be overcome practically and at least partially by RNAi silencing of CTLA4 in Teff cells.