Aug 2026· Molecular Diagnosis & Therapy· 0 citations· 249 references
Medicine
TL;DR
How cells balance this tightrope between adaptation and cell death in the context of cancer is dissected, and how UPR signaling drives angiogenesis, metastasis, immune-evasion, and chemoresistance is explored before finally discussing its therapeutic potential.
This review integrates recent mechanistic insights into UPR-driven tumor progression, including pathway crosstalk, immune regulation, and immunotherapy resistance, with advances in small-molecule inhibitors, while critically evaluating their therapeutic potential and translational challenges in cancer treatment.
Meizhen Lin, Zhijie Li· Frontiers in Immunology· 0 citations
The unfolded protein response (UPR) is a homeostatic protective mechanism activated in response to endoplasmic reticulum (ER) stress. However, once co-opted by cancer cells, its function extends far beyond maintaining proteostasis and becomes an important regulator of tumor progression. This review summarizes how the three canonical UPR branches establish a persistent adaptive state under chronic ER stress. It discusses the molecular mechanisms by which UPR signaling maintains proteostasis, reprograms cellular metabolism, alleviates oxidative stress, and coordinates autophagy. Thereby it allows cancer cells to survive in hostile microenvironments. The review further examines how these adaptive programs support tumor metastasis by promoting anoikis resistance, epithelial-mesenchymal plasticity, and tumor dormancy, which also enhances resistance to chemotherapy and immunotherapy. Current evidence suggests that cancer cell survival, metastasis, and therapy resistance are not independent consequences of UPR activation, but interconnected manifestations of a unified stress adaptation strategy driven by the UPR. By clarifying how cancer cells exploit UPR signaling and its underlying mechanisms, this review aims to provide insights into potential specific therapeutic opportunities for cancer.
Zihe Zhou· Theoretical and Natural Scie...· 0 citations
Chaperone-mediated autophagy (CMA) is a selective lysosomal degradation pathway that maintains cellular homeostasis by degrading soluble proteins containing KFERQ-like motifs. Although CMA has traditionally been recognized for its role in protein quality control and cellular stress adaptation, increasing evidence shows that it is frequently altered in cancer, where it regulates multiple processes that promote tumor initiation, progression, and therapy resistance. The growing number of identified CMA substrates involved in cell proliferation, apoptosis, metabolism, DNA damage response, immune regulation, inflammation, and cellular plasticity suggests that CMA is much more than a protein degradation pathway; it is an important regulator of tumor adaptation. In this review, we bring together current evidence to provide a comprehensive understanding of how CMA contributes to the
Hallmarks of Cancer
, including sustained proliferative signaling, resistance to cell death, metabolic reprogramming, invasion and metastasis, immune evasion, and the enabling characteristics of genome instability and tumor-promoting inflammation. We further explore the emerging roles of CMA in cellular plasticity and cancer stem cell maintenance, two interconnected processes that drive tumor progression, metastasis, and therapeutic resistance. By integrating evidence from diverse tumor types, this review provides a comprehensive understanding of how CMA shapes multiple hallmarks of cancer by selectively degrading key regulatory proteins. Finally, we highlight the context-dependent roles of CMA, identify key gaps in our current understanding, and discuss the opportunities and challenges of targeting CMA for cancer therapy. Overall, this hallmark-based perspective provides an integrated understanding of how CMA contributes to multiple hallmarks of cancer and supports its potential as a therapeutic target.
Meenakshi Tiwari, Lokendra Kumar Sharma, Bandana Chakravarti et al.· Frontiers in Oncology· 0 citations
Summary Neuroendocrine prostate cancer (NEPC) persists in a profoundly hypoxic microenvironment, yet the mechanisms enabling tumor adaptation to this metabolically challenging niche remain undefined. Here, we identify the lipid kinase PIKfyve as overexpressed in NEPC, functioning as a central node in a stress-adaptive lipid kinase axis that supports adaptation to persistent endoplasmic reticulum (ER) stress. Mechanistically, NEPC requires PIKfyve-mediated lysosomal degradation and lipid recycling to maintain metabolic homeostasis under hypoxia. PIKfyve inhibition disrupts lysosomal function, exacerbates ER stress, and activates a compensatory sterol regulatory element-binding protein (SREBP)-dependent de novo lipogenesis program essential for NEPC survival. This stress-lipid axis creates a synthetic vulnerability between PIKfyve and fatty acid synthase (FASN), where dual inhibition synergistically amplifies ER stress, triggers the terminal unfolded protein response, and induces tumor cell death. These findings reveal a metabolic adaptation in NEPC and provide preclinical evidence that co-targeting PIKfyve and FASN can overcome hypoxia-associated stress adaptation.
Yang Zheng, Caleb Cheng, Yizhi Cao et al.· Cancer Cell· 0 citations
Cancer and cardiovascular diseases, the primary causes of mortality globally, are increasingly understood as biologically interconnected rather than distinct pathologies. Recent evidence indicates that protein homeostasis (proteostasis) functions as a crucial molecular link connecting tumor progression, therapeutic resistance, cardiac remodeling, and treatment‐related cardiotoxicity. Proteostasis, which encompasses the cellular processes of protein synthesis, folding, quality control, and degradation, dictates tissue adaptation to chronic stress. Notably, the adaptive mechanisms that allow tumor cells to endure proteotoxic stress and resist therapy are often vital for maintaining cardiac structure and function. Thus, tumor control and cardiovascular injury may be divergent outcomes of a common stress–response framework. In this review, we propose proteostasis as a comprehensive framework for understanding the cancer–cardiovascular interface. We analyze how the ubiquitin–proteasome system, autophagy–lysosome pathway, endoplasmic reticulum stress‐induced unfolded protein response signaling, and molecular chaperone networks are differentially reconfigured in cancer and cardiac tissues, influencing tumor survival, therapeutic susceptibility, and cardiovascular dysfunction. Additionally, we explore the translational implications of proteostasis dysregulation, including mechanisms of anticancer therapy‐induced cardiotoxicity, emerging biomarkers, cardioprotective strategies, and opportunities for precision cardio‐oncology. By conceptualizing efficacy and toxicity as interconnected outcomes of shared proteostasis biology, this review establishes a foundation for developing therapies that optimize cancer control while safeguarding cardiovascular health.
Jacob Eli García Torres, Norbert Frey, A. Rangrez· MedComm· 0 citations
In insights on the research regarding therapeutic approaches of NDs which intend to target molecular components, a general understanding of proteostasis, ER stress, UPR signalling and how these cellular processes are related to neurodegeneration is provided.
E. Çoban, A. Cerkezkayabekir· Neurochemical Journal· 0 citations