Chloroquine Overcomes Chemotherapy Resistance and Suppresses Cancer Metastasis by Eradicating Dormant Cancer Cells

Tumor cell resistance to anticancer therapy and tumor relapse remain major challenges in cancer treatment. Chloroquine, an FDA-approved antimalarial drug currently undergoing clinical trials for various cancers, has emerged as a promising candidate for combination therapy with conventional anticancer agents. In this study, we demonstrate that in patients-derived osteosarcoma cells who had undergone multiple chemotherapy treatments, as well as in murine colorectal cancer cells, administration of standard chemotherapeutic agents induces autophagy, which likely serves as a cytoprotective mechanism promoting therapy resistance in at least of part of tumor population. Incorporating chloroquine into the treatment regimen effectively suppressed autophagy, significantly enhancing osteosarcoma cell death in both 2D and 3D models while simultaneously reducing cell proliferation and migration capacity. In an orthotopic in vivo model of colorectal cancer, the combination of chloroquine and oxaliplatin not only impaired tumor growth but also prevented metastatic dissemination and inhibited the formation of metastasis. Notably, comparative analyses of proliferating and dormant tumor cell populations revealed that chloroquine exerts preferential cytotoxicity toward dormant cancer cells. This suggests a dual therapeutic advantage, wherein cytostatic agents primarily eliminate proliferating cells, while chloroquine specifically eradicates dormant cancer cells, which are often implicated in tumor recurrence. Collectively, these findings highlight the potential of autophagy inhibition to enhance the chemotherapy efficacy and suggest chloroquine-based combination therapy as a promising strategy for suppressing tumor growth and metastasis, ultimately improving treatment outcomes in cancer patients.