The molecular arms race: Xenophagy, pathogen evasion, and emerging host-directed therapies

Xenophagy, a form of selective autophagy targeting intracellular pathogens, constitutes a central arm of cell-autonomous innate immunity. This review synthesizes recent advances in the molecular regulation of xenophagy, emphasizing ubiquitin-dependent and ubiquitin-independent cargo tagging, receptor redundancy and context dependence, and post-translational control of autophagy-related 8/microtubule-associated protein 1 light chain 3 (ATG8/MAP1LC3/LC3) engagement. We discuss how pathogens exploit or evade xenophagic defenses at multiple checkpoints, cargo recognition, receptor recruitment, autophagosome biogenesis, and lysosomal fusion, highlighting mechanistically defined bacterial and viral countermeasures. Attention is given to the distinction between canonical xenophagy and non-canonical LC3-associated phagocytosis (LAP), clarifying their divergent regulatory logic and functional outcomes. We further examine the integration of xenophagy with innate immune signaling, antigen processing and presentation, and intercellular communication via exosomes, thereby linking intracellular pathogen restriction to adaptive immunity. Emerging discovery platforms, including multi-omics and clustered regularly interspaced short palindromic repeats (CRISPR-based) genetic screens, are evaluated for their potential to uncover novel xenophagy regulators. Finally, we critically assess translational opportunities for xenophagy-targeted host-directed therapies, emphasizing pathogen-specific context, tissue-restricted delivery, and the risks of non-selective autophagy modulation. Together, this review provides a mechanistic and translational framework for understanding xenophagy as a dynamic, context-dependent immune defense pathway rather than a uniformly protective degradative process.