The primordial autophagy process, originally identified as a starvation response in baker’s yeast, has since been shown to have a wide spectrum of functions other than survival. In many cases, it is accepted that autophagy operates as a key tumor suppressor mechanism that protects cells from adverse environmental cues by enforcing homeostasis and maintaining the functional and structural integrity of organelles. Paradoxically, heightened states of autophagy are also seen in some cancers, leading to the prevailing view that the pro-survival aspect of autophagy might be hijacked by some tumors to promote their fitness and pathogenesis. Notably, recent studies have revealed a broad range of cell-autonomous autophagy in reshaping tumor microenvironment and maintaining lineage integrity and immune homeostasis, calling for a renewed understanding of autophagy beyond its classical roles in cell survival. Here, we evaluate the increasing body of literature that argues the “double-edged” consequences of autophagy manipulation in cancer therapy, with a particular focus on highly plastic and mutagenic melanoma. We also discuss the caveats that must be considered when evaluating whether autophagy blockade is the effector mechanism of some anti-cancer therapy particularly associated with lysosomotropic agents. If autophagy proteins are to be properly exploited as targets for anticancer drugs, their diverse and complex roles should also be considered.
