Autophagy (Greek for self-eating) is the process transporting intracellular misfolded proteins, damaged organelles, and other macromolecular substances to lysosomes for degradation which is first proposed by Christian de Duve in 1963 (Mizushima, 2007). Autophagy is generally divided into three types: macroautophagy, microautophagy, and chaperone-mediated autophagy. Macroautophagy, referred to herein as “autophagy”, is the most prevalent form of autophagy. Under physiological conditions, cells maintain a low level of autophagy, while the level is primarily elevated under stress such as nutrient deprivation, hypoxia, or infection (Dikic & Elazar, 2018). Autophagy helps the cells remove intracellular substances including damaged mitochondria and endoplasmic reticulum, which is critical for maintaining cellular homeostasis and providing additional nutrients and energy for cell survival (Dikic & Elazar, 2018).

Autophagy is involved in various signal pathways and cellular processes, while defects in autophagy may result in the emergence of different diseases, such as neurodegenerative diseases, aging, and liver diseases (Levine & Kroemer, 2008). In particular, the contribution of autophagy to tumorigenesis is complex and controversial (Kimmelman, 2011; Long & McWilliams, 2020). Autophagy plays a dual role in the context of different types and stages of cancers (Cristofani et al., 2018). At the early stage, autophagy induction might prevent cancer development (Levine & Kroemer, 2019). Conversely, in established tumors, autophagy activation promotes tumorigenesis and metastasis by reducing DNA damage, maintaining mitochondrial function, and providing substrates for cell metabolism in the microenvironment of ischemia and hypoxia, as well as assisting the anoikis resistance (White, 2012). Autophagy induction is found in the tumors in patients with different cancers, as evidenced by the increased expression of autophagy biomarkers.

Chemotherapy remains by far one of the most used approaches for the treatment of cancers. However, the majority of failure in chemotherapy is related to drug resistance. Though mechanisms of chemoresistance are quite complicated, autophagy induction has been recognized as one of the causes of drug resistance in several types of cancers (Chandra, Rick, Yagnik, & Aghi, 2020; Poillet-Perez, Sarry, & Joffre, 2021). Autophagy is beneficial for the survival of cancer cells under the stress of chemotherapy by repairing damaged DNA and removing toxic organelles and proteins. Autophagy induction is suggested to be the mechanism of drug resistance for conventional cytotoxic drugs including paclitaxel (Peng et al., 2014), docetaxel (DTX) (Hu et al., 2018), cisplatin (Wang & Wu, 2014), oxaliplatin (Wang et al., 2021), doxorubicin (DOX) (Zhang et al., 2022), and 5-fluorouracil (5-FU) (Fang et al., 2022). Autophagy inhibition can restore the sensitivity of cancer cells to chemotherapeutic drugs (Levy, Towers, & Thorburn, 2017). Either autophagy inhibitors including chloroquine (CQ), hydroxychloroquine (HCQ), and 3-methyladenine (3-MA) (Amaravadi et al., 2007; Fang et al., 2022; Liu et al., 2019; Wang, Wang, Zhang, et al., 2021) or knockdown of autophagic proteins including Beclin 1, ATG7, ATG10, and ATG14 (Lin et al., 2020; Luo et al., 2021; Sun et al., 2020) could enhance the anticancer effect of these chemotherapeutic drugs.

Autophagy inhibitors for cancer therapy are limited due to the rapid clearance, poor accumulation in the tumor sites, and side effects associated with high doses. Recently, nanomedicines have shown great potential in the diagnosis and therapy of cancer. Owing to the enhanced permeability and retention (EPR) effect, nanomaterials preferentially accumulate in tumors with leaking and hyperpermeable vasculatures. The nanomaterials can also be conjugated with targeting agents enabling selective delivery of anticancer drugs into the tumors (Nie, Xing, Kim, & Simons, 2007). The albumin-bound paclitaxel formulation (Abraxane) has been approved by the U.S. Food and Drug Administration (FDA) for treating metastatic breast cancer, non-small cell lung cancer (NSCLC), and advanced pancreatic cancer. In the past several years, nanomaterials are reported to deliver autophagy inhibitors to improve their therapeutic performances. Moreover, nanomaterials are also found to regulate autophagy (Stern, Adiseshaiah, & Crist, 2012). Once they enter cells, they are mainly distributed in the lysosomes, thus affecting autophagy-lysosome pathway. Silver nanoparticles (NPs) (Lin et al., 2014), cerium oxide (Song et al., 2014), and cadmium selenide/zinc sulfide quantum dots (QDs) (Chen et al., 2013) are reported as autophagy inducers. On the other hand, nanomaterials such as gold, silver, iron oxide, zinc oxide (ZnO), and polymeric NPs are identified as autophagy inhibitors. The role of nanomaterials in autophagy regulation is highly related to cell types and the physicochemical properties of nanomaterials. As for autophagy inhibition, nanomaterials cause lysosome dysfunction due to their surface charge, ion release and retention, and the affinity to lysosomal proteins, thus leading to the impairment of autophagic degradation. Besides, some nanomaterials or their products are released or diffused into the cytosol to affect autophagosome maturation, autophagosome-lysosome fusion, and the late stage of autophagy process. Nanomaterials are thus identified as a new type of autophagy inhibitors.

In this review, we briefly introduce the autophagy process and molecular mechanisms. Then we focus on the recent progress of various small molecule compounds and nanomaterials in inhibiting autophagy. Their molecular mechanisms for autophagy inhibition are illustrated. The drug delivery systems of autophagy inhibitors and their advantages over free drugs are also described. Finally, the current progress of clinical trials of autophagy inhibitors is introduced, and the insights and future perspectives of autophagy inhibitors are provided.