This study investigates the role of autophagy in a Myc-induced model of lymphoma, where tumors are resistant to apoptosis due to the lack of nuclear p53. Systemic administration of tamoxifen (TAM) activates p53, leading to tumor regression followed by recurrence. Inhibition of autophagy with chloroquine (CQ) or ATG5 short hairpin RNA (shRNA) enhances the ability of p53 activation or alkylating drug therapy to induce tumor cell death. The results provide evidence that autophagy serves as a survival pathway in tumor cells treated with apoptosis activators and suggest that autophagy inhibitors like CQ can be used in combination with therapies designed to induce apoptosis in human cancers.This study investigates the role of autophagy in a Myc-induced model of lymphoma, where tumors are resistant to apoptosis due to the lack of nuclear p53. Systemic administration of tamoxifen (TAM) activates p53, leading to tumor regression followed by recurrence. Inhibition of autophagy with chloroquine (CQ) or ATG5 short hairpin RNA (shRNA) enhances the ability of p53 activation or alkylating drug therapy to induce tumor cell death. The results provide evidence that autophagy serves as a survival pathway in tumor cells treated with apoptosis activators and suggest that autophagy inhibitors like CQ can be used in combination with therapies designed to induce apoptosis in human cancers.