Autophagy inhibition enhances therapy-induced apoptosis in a Myc-induced model of lymphoma. Autophagy, a lysosome-dependent degradation pathway, is frequently activated in tumor cells treated with chemotherapy or radiation. Whether autophagy in treated cancer cells represents a survival mechanism or a nonapoptotic form of programmed cell death remains controversial. This study examines the role of autophagy in a Myc-induced lymphoma model derived from p53ER/TAM mice, which lack nuclear p53 and are resistant to apoptosis. Systemic tamoxifen administration activates p53, leading to tumor regression and subsequent recurrence. Autophagy is induced in surviving cells, and its inhibition with chloroquine or ATG5 shRNA enhances p53 activation or alkylating drug therapy-induced apoptosis. These findings suggest that autophagy serves as a survival pathway in tumor cells treated with apoptosis activators, and that autophagy inhibitors like chloroquine may enhance the efficacy of apoptosis-inducing therapies in human cancers. The study demonstrates that autophagy can be an adaptive mechanism that contributes to tumor cell survival and resistance to therapy-induced apoptosis. Activation of p53 in Myc/p53ER TAM tumors induces apoptosis, and surviving tumor cells exhibit active autophagy. Impairment of autophagic vesicle clearance by the lysosomotropic drug chloroquine correlates with enhanced apoptosis and tumor regression, as well as delayed tumor recurrence. This is likely due to a direct prosurvival effect of autophagy in tumor cells, as autophagy inhibition by either ATG5 shRNA or chloroquine enhances tumor cell apoptosis and suppresses tumor cell recovery when p53 is induced in vitro. Chloroquine disrupts lysosomal function, inhibiting the last critical step in autophagy, the acid-dependent degradation of autophagosome contents, leading to the accumulation of autophagic vesicles that cannot be cleared. Although chloroquine at higher doses may have additional detrimental effects on tumor cell viability, the doses studied here failed to cause tumor regression in vivo or induce the death of tumor cells in vitro. The ability of chloroquine to augment tumor cell death in response to p53 activation or alkylating drug therapy correlates with its ability to impair autophagy. A similar augmentation of tumor cell death in response to p53 activation or alkylating drug therapy was observed in cells in which autophagy is genetically suppressed by shATG5. Chloroquine treatment failed to further augment cell death in cells lacking functional autophagy following p53 activation or alkylating drug therapy. Thus, at the doses studied here, inhibition of autophagy is likely the basis of chloroquine's major antineoplastic effect. The study provides evidence that autophagy can be an adaptive response that allows cancer cells to survive an apoptotic stimulus that would otherwise lead to their demise. The ability of tumorAutophagy inhibition enhances therapy-induced apoptosis in a Myc-induced model of lymphoma. Autophagy, a lysosome-dependent degradation pathway, is frequently activated in tumor cells treated with chemotherapy or radiation. Whether autophagy in treated cancer cells represents a survival mechanism or a nonapoptotic form of programmed cell death remains controversial. This study examines the role of autophagy in a Myc-induced lymphoma model derived from p53ER/TAM mice, which lack nuclear p53 and are resistant to apoptosis. Systemic tamoxifen administration activates p53, leading to tumor regression and subsequent recurrence. Autophagy is induced in surviving cells, and its inhibition with chloroquine or ATG5 shRNA enhances p53 activation or alkylating drug therapy-induced apoptosis. These findings suggest that autophagy serves as a survival pathway in tumor cells treated with apoptosis activators, and that autophagy inhibitors like chloroquine may enhance the efficacy of apoptosis-inducing therapies in human cancers. The study demonstrates that autophagy can be an adaptive mechanism that contributes to tumor cell survival and resistance to therapy-induced apoptosis. Activation of p53 in Myc/p53ER TAM tumors induces apoptosis, and surviving tumor cells exhibit active autophagy. Impairment of autophagic vesicle clearance by the lysosomotropic drug chloroquine correlates with enhanced apoptosis and tumor regression, as well as delayed tumor recurrence. This is likely due to a direct prosurvival effect of autophagy in tumor cells, as autophagy inhibition by either ATG5 shRNA or chloroquine enhances tumor cell apoptosis and suppresses tumor cell recovery when p53 is induced in vitro. Chloroquine disrupts lysosomal function, inhibiting the last critical step in autophagy, the acid-dependent degradation of autophagosome contents, leading to the accumulation of autophagic vesicles that cannot be cleared. Although chloroquine at higher doses may have additional detrimental effects on tumor cell viability, the doses studied here failed to cause tumor regression in vivo or induce the death of tumor cells in vitro. The ability of chloroquine to augment tumor cell death in response to p53 activation or alkylating drug therapy correlates with its ability to impair autophagy. A similar augmentation of tumor cell death in response to p53 activation or alkylating drug therapy was observed in cells in which autophagy is genetically suppressed by shATG5. Chloroquine treatment failed to further augment cell death in cells lacking functional autophagy following p53 activation or alkylating drug therapy. Thus, at the doses studied here, inhibition of autophagy is likely the basis of chloroquine's major antineoplastic effect. The study provides evidence that autophagy can be an adaptive response that allows cancer cells to survive an apoptotic stimulus that would otherwise lead to their demise. The ability of tumor