Protein Homeostasis Networks in Lymphoid Malignancies: Mechanisms of Proteostasis Addiction and Therapeutic Vulnerabilities

Lymphoid malignancies comprise a diverse group of hematologic cancers characterized by extensive genetic, epigenetic, and microenvironmental heterogeneity. Despite substantial advances in targeted therapies and immunotherapeutic approaches, disease relapse and therapeutic resistance remain major clinical challenges. Increasing evidence suggests that malignant lymphoid cells are highly dependent on protein homeostasis (proteostasis) networks to cope with the elevated proteotoxic stress imposed by oncogenic signaling, rapid proliferation, immunoglobulin synthesis, and microenvironmental stressors. This dependence, often referred to as proteostasis addiction, represents a critical vulnerability that can be therapeutically exploited. Proteostasis is maintained through an integrated network that regulates protein synthesis, folding, quality control, and degradation. In lymphoid malignancies, dysregulation of these pathways drives adaptive responses involving molecular chaperones, the unfolded protein response (UPR), the ubiquitin–proteasome system (UPS), and autophagy–lysosome pathways. These mechanisms collectively enable tumor cells to survive conditions that would otherwise induce proteotoxic collapse and cell death. Notably, the clinical success of proteasome inhibitors in plasma cell neoplasms has provided proof of concept that targeting proteostasis can yield meaningful therapeutic benefit. In this review, we discuss the major sources of proteotoxic stress in lymphoid malignancies and summarize the molecular mechanisms that sustain proteostasis addiction. We further examine current and emerging therapeutic strategies aimed at disrupting proteostasis networks, including proteasome inhibitors, UPR-targeted agents, chaperone-directed therapies, and novel targeted protein degradation technologies. Finally, we highlight the contribution of proteostasis remodeling to therapeutic resistance and discuss future opportunities for biomarker development and precision medicine. A deeper understanding of proteostasis dependencies may facilitate the identification of novel therapeutic vulnerabilities and improve outcomes for patients with lymphoid malignancies.