Most commonly recognized as a catabolic pathway, autophagy is a perplexing mechanism through which a living cell can free itself of excess cytoplasmic components, i.e., organelles, by means of certain membranous vesicles or lysosomes filled with degrading enzymes. Upon exposure to external insult or internal stimuli, the cell might opt to activate such a pathway, through which it can gain control over the maintenance of intracellular components and thus sustain homeostasis by intercepting the formation of unnecessary structures or eliminating the already present dysfunctional or inutile organelles. Despite such appropriateness, autophagy might also be considered a frailty for the cell, as it has been said to have a rather complicated role in tumorigenesis. A merit in the early stages of tumor formation, autophagy appears to be salutary because of its tumor-suppressing effects. In fact, several investigations on tumorigenesis have reported diminished levels of autophagic activity in tumor cells, which might result in transition to malignancy. On the contrary, autophagy has been suggested to be a seemingly favorable mechanism to progressed malignancies, as it contributes to survival of such cells. Based on the recent literature, this mechanism might also be activated upon the entry of engineered nanomaterials inside a cell, supposedly protecting the host from foreign materials. Accordingly, there is a good chance that therapeutic interventions for modulating autophagy in malignant cells using nanoparticles may sensitize cancerous cells to certain treatment modalities, e.g., radiotherapy. In this review, we will discuss the signaling pathways involved in autophagy and the significance of the mechanism itself in apoptosis and tumorigenesis while shedding light on possible alterations in autophagy through engineered nanomaterials and their potential therapeutic applications in cancer. SIGNIFICANCE STATEMENT: Autophagy has been said to have a complicated role in tumorigenesis. In the early stages of tumor formation, autophagy appears to be salutary because of its tumor-suppressing effects. On the contrary, autophagy has been suggested to be a favorable mechanism to progressed malignancies. This mechanism might be affected upon the entry of nanomaterials inside a cell. Accordingly, therapeutic interventions for modulating autophagy using nanoparticles may sensitize cancerous cells to certain therapies.