Risk factors of using late-autophagy inhibitors: Aspects to consider when combined with anticancer therapies

Cancer resistance to therapy is still an unsolved scientific and clinical problem. In 2022, the hallmarks of cancer have been expanded to include four new features, including cellular senescence. Therapy-induced senescence (TIS) is a stressor-based response to conventional treatment methods, e.g. chemo- and radiotherapy, but also to non-conventional targeted therapies. Since TIS reinforces resistance in cancers, new strategies for sensitizing cancer cells to therapy are being adopted. These include macroautophagy as a potential target for inhibition due to its potential cytoprotective role in many cancers. The mechanism of late-stage autophagy inhibitors is based on blockage of autophagolysosome formation or an increase in lysosomal pH, resulting in disrupted cargo degradation. Such inhibitors are relevant candidates for increasing anticancer therapy effectiveness. In particular, 4-aminoquoline derivatives: chloroquine/hydroxychloroquine (CQ/HCQ) have been tested in multiple clinical trials in combination with senescence-inducing anti-cancer drugs. In this review, we summarize the properties of selected late-autophagy inhibitors and their role in the regulation of autophagy and senescent cell phenotype in vitro and in vivo models of cancer as well as treatment response in clinical trials on oncological patients. Additionally, we point out that, although these compounds increase the effectiveness of treatment in some cases, their practical usage might be hindered due to systemic toxicity, hypoxic environment, dose- ant time-dependent inhibitory effects, as well as a possible contribution to escaping from TIS.