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Simple Summary The modulation of autophagy represents a potential therapeutic strategy for cancer. More than one hundred clinical trials have been conducted or are ongoing to explore the efficacy of autophagy modulators to reduce the tumor growth and potentiate the anti-cancer effects of conventional therapy. Despite this, the effective role of autophagy during tumor initiation, growth, and metastasis remains not well understood. Depending on the cancer type and stage of cancer, autophagy may have tumor suppressor properties as well as help cancer cells to proliferate and evade cancer therapy. The current review aims to summarize the current knowledge about the autophagy implications in cancer and report the therapeutic opportunities based on the modulation of the autophagy process. Abstract The malignant transformation of a cell produces the accumulation of several cellular adaptions. These changes determine variations in biological processes that are necessary for a cancerous cell to survive during stressful conditions. Autophagy is the main nutrient recycling and metabolic adaptor mechanism in eukaryotic cells, represents a continuous source of energy and biomolecules, and is fundamental to preserve the correct cellular homeostasis during unfavorable conditions. In recent decades, several findings demonstrate a close relationship between autophagy, malignant transformation, and cancer progression. The evidence suggests that autophagy in the cancer context has a bipolar role (it may act as a tumor suppressor and as a mechanism of cell survival for established tumors) and demonstrates that the targeting of autophagy may represent novel therapeutic opportunities. Accordingly, the modulation of autophagy has important clinical benefits in patients affected by diverse cancer types. Currently, about 30 clinical trials are actively investigating the efficacy of autophagy modulators to enhance the efficacy of cytotoxic chemotherapy treatments. A deeper understanding of the molecular pathways regulating autophagy in the cancer context will provide new ways to target autophagy for improving the therapeutic benefits. Herein, we describe how autophagy participates during malignant transformation and cancer progression, and we report the ultimate efforts to translate this knowledge into specific therapeutic approaches to treat and cure human cancers.

One of the greatest goals in medicine is early-stage detection of tumors, to allow physicians and surgeons to apply the available therapies, which are usually successful on small volume cancers only. [...]