Autophagy is an intracellular degradation and recycling mechanism that preserves cellular homeostasis by breaking down damaged organelles and protein aggregates via lysosomes.(p1) In the past few years, the function of autophagy in cancer has attracted widespread attention. On one hand, autophagy can inhibit tumor development by clearing damaged organelles and suppressing inflammatory responses; on the other hand, cancer cells might harness autophagy to acclimatize to hypoxic and nutrient-poor microenvironments, thereby promoting tumor viability and growth.(p2) The Janus roles of autophagy endow it with complex clinical significance in cancer therapy, making it a potential mechanism for tumor resistance.

Protein kinases play a key part in the regulation of autophagy. They precisely control the initiation, elongation and termination of autophagy by phosphorylating autophagy-related proteins to modulate their activity, localization and stability.(p3) Under conditions such as nutrient deprivation and oxidative stress, protein kinases regulate autophagy to ensure cellular homeostasis. For example, the mechanistic target of rapamycin (mTOR) kinase inhibits autophagy when nutrients are abundant but relieves this inhibition under nutrient-deprived conditions to regulate cellular energy demands.(p4) Small-molecule modulators of protein kinases are capable of specifically targeting protein kinases to regulate their activity, thereby influencing the autophagy process. By precisely modulating autophagy, these small-molecule modulators can induce apoptosis in tumor cells or inhibit tumor growth.(p5) Therefore, the development and application of small-molecule modulators of protein kinases hold great promise for cancer treatment.

In this context, we employ the term ‘Janus roles’ to specifically describe the opposing, context-dependent functions of a single kinase, which can switch between promoting and suppressing autophagy based on cellular conditions. This concept moves beyond a simple ‘dual role’ by emphasizing the dynamic and conditional nature of the regulation. This review systematically dissects the Janus roles of protein kinases in autophagy and explores the anticancer potential of small-molecule modulators that target them. We further propose novel therapeutic strategies based on this regulatory axis.