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Purpose:Autophagy is the major regulated mechanism for degrading long lived proteins and the only known pathway for degrading organelles in cell.In this work,we studied the impact of autophagy inhibitor chloroquine(CQ)combined with high-LET carbon ions on the radiosensitivity of tumor to heavy ions.Methods:Kunming mice were orthotopically implanted with S180 tumor and randomly divided into control,treated with CQ alone,irradiation alone and irradiation combined with CQ pretreatment groups.The irradiations were conducted with carbon ions(LET=75keV/μm)at a dose of 2Gy.Mice were sacrificed at 3 or 15 days post-irradiation and the tumors were stripped for further experiments.Results:The carbon ions irradiation combined with CQ caused more severe tumor tissue lesions than the irradiation alone.The irradiation alone caused just a slight increase in the ratio of apoptotic cells,while the combined treatment increased the ratio of apoptotic cells significantly.The results showed that heavy ion radiation induced both apoptosis and autophagy in mouse sarcoma cell S180 line through a mechanism that involved endoplasmic reticulum(ER)stress.Moreover,inhibition of autophagy with CQ enhanced cell death in high-LET radiated cell lines.The combination of heavy ion with the autophagy inhibitor chloroquine produced more pronounced tumor suppression in S180 sarcoma both in vivo and in vitro.Conclusion:The result of the present work implied that both ER stress and autophagy were involved in the cell death induced by radiation.For high-LET heavy ions,inhibition of autophagy with CQ could enhance tumor cell apoptosis,leading to an increase in radiosensitivity.Modulation of autophagy with specific inhibitor such as CQ is a promising therapeutic strategy in cancer treatment.