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Treat. Options in Oncol. (2023) 24:130–145 DOI 10.1007/s11864-023-01053-8  \nSkin Cancer (T Ito, Section Editor)  \nAutophagy Paradox: Strategizing Treatment Modality in Melanoma  \nChristian Pangilinan, PhD1  Xiaowei Xu, MD, PhD2 Meenhard Herlyn, DVM, DSc1  \nChengyu Liang, MD, PhD1,*   \nAddress  \n*,1Molecular and Cellular Oncogenesis Program, The Wistar Institute, 3601 Spruce Street, Philadelphia, PA, 19104, USA  \nEmail: [cliang@wistar.org](cliang@wistar.org)  \n2Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA  \nPublished online: 21 January 2023  \n* The Author(s) 2023 . This article is an open access publication  \nThis article is part of the Topical Collection on Skin Cancer  \nKeywords Skin cancer I Melanoma I Autophagy I Lysosome I Targeted therapy I Immunotherapy  \nOpinion statement  \nThe 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 cellautonomous 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  \n.  \n\n| Introduction |  |\n| --- | --- |\n| Melanoma is the malignancy of pigment-producing me- | most have only achieved partial clinical responses or |\n| lanocytes of the skin and rarely, the uveal layer of the | work in a subset of patients, suggesting that melanoma |\n| eye. Though constituting only a small proportion of all | pathogenesis is far more complex than the intrinsic |\n| skin cancer types, melanoma is deemed as the most fatal | genetic determinants. Indeed, a growing body of evi- |\n| form ranking among top 5 in the US 2022 estimated | dence indicates that non-genetic mechanisms also con- |\n| leading cancer cases and deaths [1] . Genetic alterations, | tribute to melanoma persistence, resistance, and/or re- |\n| primarily affecting the mitogen-activated protein kinase | currence, which operate in a broad range of biological |\n| (MAPK) signaling pathway, have been identified in mel- | processes, including metabolic reprogramming, pheno- |\n| anoma, majority of which is clustered on gain-of- | typic switching, and immune microenvironment re- |\n| function mutations in BRAF, a cell-signaling molecule | modeling [6] . Understanding the unique biology and |\n| that regulates the MAPK pathway [2] . Despite tremen- | evolution of melanoma over space and time is crucial to |\n| dous advancements with BRAF-targeted therapies and | the development of more effective and durable therapies |\n| immune checkpoint inhibitors [3], the clinical benefit | for melanoma treatment. It is within this context that we |\n| of these current treatment modalities for melanoma is | discuss some of the current contrasting paradigms on |\n| curbed by the al","cbCaitSuTJo1qIsc","https://ap.wps.com/l/cbCaitSuTJo1qIsc","pdf",721657,16,"English","# Opinion statement\n## Introduction\n## Autophagy: a landscape beyond survival and death","[{\"question\":\"Why is autophagy described as having a “double-edged” role in cancer therapy?\",\"answer\":\"Autophagy can act as a tumor-suppressing mechanism that enforces homeostasis, yet heightened autophagy states are also observed in some cancers. Some tumors may hijack the pro-survival aspect of autophagy to promote fitness and disease progression.\"},{\"question\":\"How do different forms of autophagy relate to lysosomes?\",\"answer\":\"Autophagy is classified into chaperone-mediated autophagy, microautophagy, and macroautophagy, all sharing the terminal station of lysosomes. Each type uses distinct upstream mechanisms to deliver substrates to lysosomes for degradation.\"},{\"question\":\"What should be considered when evaluating whether autophagy blockade is responsible for anti-cancer effects?\",\"answer\":\"The article discusses caveats, particularly for therapies associated with lysosomotropic agents, because the effector mechanism may not be explained solely by autophagy inhibition. Evaluating autophagy blockade requires accounting for the broader context of drug action and biology.\"}]","Autophagy Paradox - Strategizing Treatment Modality in Melanoma | PDF",1790269468]