Autophagy, a cellular process that degrades damaged components via lysosomes, plays a dual role in cancer treatment. It can act as a cytoprotective mechanism, enhancing tumor progression, or as a cytotoxic mechanism, increasing sensitivity to therapeutic agents. This duality has sparked renewed interest in developing novel cancer therapies. The review highlights the complex interplay between autophagy and cancer, emphasizing the need for a deeper understanding of its molecular mechanisms. Autophagy-related genes and secreted factors can promote drug resistance by activating autophagy. For example, suppressing ATG4A in breast cancer cells improved tamoxifen response, while SH3BGRL enhanced doxorubicin resistance by promoting PIK3C3 translation and ATG12 stability. Similarly, EVI1 upregulates ATG7, impairing imatinib sensitivity in leukemia. Autophagy induction via ATG5 upregulation promotes resistance to fluorouracil in gastric cancer, and Sestrin2 induces autophagy, enhancing resistance to oxaliplatin in osteosarcoma. Circulating RNAs and long non-coding RNAs also contribute to drug resistance through autophagy activation. For instance, Hsa_circ_0092276 promotes doxorubicin resistance in breast cancer, while lncRNA XIST enhances carboplatin resistance in ovarian cancer. The tumor microenvironment influences autophagy, with immune cells infiltrating tumors being shaped by autophagy to support tumor progression. Autophagy inhibition can repolarize macrophages, enhancing chemosensitivity to cisplatin. Stress factors like ER stress can trigger autophagy, promoting therapeutic resistance. Insulin resistance and microbiota also influence autophagy, affecting drug resistance. Conversely, autophagy activation can improve therapeutic outcomes. For example, rapamycin enhances breast cancer response to adriamycin, while miR-519a improves glioblastoma sensitivity to temozolomide. Autophagy activation can also enhance immunotherapy efficacy by boosting antitumor immunity and sensitizing cancer cells to checkpoint inhibitors. The dual role of autophagy in cancer treatment necessitates careful consideration of its activation or inhibition. While autophagy inhibitors may benefit patients with upregulated autophagy, activation may be more effective for those with downregulated autophagy. Further research is needed to determine optimal strategies for autophagy modulation in cancer therapy.Autophagy, a cellular process that degrades damaged components via lysosomes, plays a dual role in cancer treatment. It can act as a cytoprotective mechanism, enhancing tumor progression, or as a cytotoxic mechanism, increasing sensitivity to therapeutic agents. This duality has sparked renewed interest in developing novel cancer therapies. The review highlights the complex interplay between autophagy and cancer, emphasizing the need for a deeper understanding of its molecular mechanisms. Autophagy-related genes and secreted factors can promote drug resistance by activating autophagy. For example, suppressing ATG4A in breast cancer cells improved tamoxifen response, while SH3BGRL enhanced doxorubicin resistance by promoting PIK3C3 translation and ATG12 stability. Similarly, EVI1 upregulates ATG7, impairing imatinib sensitivity in leukemia. Autophagy induction via ATG5 upregulation promotes resistance to fluorouracil in gastric cancer, and Sestrin2 induces autophagy, enhancing resistance to oxaliplatin in osteosarcoma. Circulating RNAs and long non-coding RNAs also contribute to drug resistance through autophagy activation. For instance, Hsa_circ_0092276 promotes doxorubicin resistance in breast cancer, while lncRNA XIST enhances carboplatin resistance in ovarian cancer. The tumor microenvironment influences autophagy, with immune cells infiltrating tumors being shaped by autophagy to support tumor progression. Autophagy inhibition can repolarize macrophages, enhancing chemosensitivity to cisplatin. Stress factors like ER stress can trigger autophagy, promoting therapeutic resistance. Insulin resistance and microbiota also influence autophagy, affecting drug resistance. Conversely, autophagy activation can improve therapeutic outcomes. For example, rapamycin enhances breast cancer response to adriamycin, while miR-519a improves glioblastoma sensitivity to temozolomide. Autophagy activation can also enhance immunotherapy efficacy by boosting antitumor immunity and sensitizing cancer cells to checkpoint inhibitors. The dual role of autophagy in cancer treatment necessitates careful consideration of its activation or inhibition. While autophagy inhibitors may benefit patients with upregulated autophagy, activation may be more effective for those with downregulated autophagy. Further research is needed to determine optimal strategies for autophagy modulation in cancer therapy.