Ubiquitin-driven regulation of immune checkpoints in lung cancer: Mechanisms and therapeutic implications (Review).

The ubiquitin-proteasome system is a master regulator of anti-tumor immunity in lung cancer, which primarily functions through controlling the stability of immune checkpoint proteins. The present review offers a synthesis concerning how a dynamic balance between E3 ubiquitin ligases (E3s) and deubiquitinases (DUBs) dictates the fate of key checkpoint proteins, including programmed cell death protein 1/programmed death-ligand 1, lymphocyte-activating gene 3 and B7 homolog 4. Although specific E3s are known to promote checkpoint degradation to enhance T-cell function in certain contexts, and DUBs frequently stabilize these proteins to foster immune evasion, these effects are context-dependent; for example, certain E3s are paradoxically able to promote immune evasion, whereas the inhibition of select DUBs synergizes with immune checkpoint blockade. This regulatory interplay extends to core oncogenic pathways, including the phosphoinositide 3-kinase/AKT and mitogen-activated protein kinase signaling pathways, which indirectly modulate checkpoint expression. Therapeutically, targeting these enzymes with various agents, such as the ubiquitin-specific peptidase 7 inhibitor P5091 or the repurposed drug canagliflozin, has the effect of synergizing with immune checkpoint blockade through reshaping the tumor microenvironment. However, clinical translation is challenged by tumor heterogeneity, pathway redundancy and the complexity of the ubiquitin network. Future progress in this area hinges on precision drug design, predictive biomarker development and rational combination therapies that are informed by a deeper mechanistic understanding of ubiquitin-driven immune regulation.