Modulation of Cancer Cell Autophagic Responses by Graphene-Based Nanomaterials: Molecular Mechanisms and Therapeutic Implications

SIMPLE SUMMARY: Graphene-based nanomaterials (GNM) are one-to-several carbon atom-thick flakes of graphite with at least one lateral dimension <100 nm. The unique electronic structure, high surface-to-volume ratio, and relatively low toxicity make GNM potentially useful in cancer treatment. GNM such as graphene, graphene oxide, graphene quantum dots, and graphene nanofibers are able to induce autophagy in cancer cells. During autophagy the cell digests its own components in organelles called lysosomes, which can either kill cancer cells or promote their survival, as well as influence the immune response against the tumor. However, a deeper understanding of GNM-autophagy interaction at the mechanistic and functional level is needed before these findings could be exploited to increase GNM effectiveness as cancer therapeutics and drug delivery systems. In this review, we analyze molecular mechanisms of GNM-mediated autophagy modulation and its possible implications for the use of GNM in cancer therapy. ABSTRACT: Graphene-based nanomaterials (GNM) are plausible candidates for cancer therapeutics and drug delivery systems. Pure graphene and graphene oxide nanoparticles, as well as graphene quantum dots and graphene nanofibers, were all able to trigger autophagy in cancer cells through both transcriptional and post-transcriptional mechanisms involving oxidative/endoplasmic reticulum stress, AMP-activated protein kinase, mechanistic target of rapamycin, mitogen-activated protein kinase, and Toll-like receptor signaling. This was often coupled with lysosomal dysfunction and subsequent blockade of autophagic flux, which additionally increased the accumulation of autophagy mediators that participated in apoptotic, necrotic, or necroptotic death of cancer cells and influenced the immune response against the tumor. In this review, we analyze molecular mechanisms and structure–activity relationships of GNM-mediated autophagy modulation, its consequences for cancer cell survival/death and anti-tumor immune response, and the possible implications for the use of GNM in cancer therapy.