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.
Abstract
Endoplasmic reticulum (ER) stress, triggered by the accumulation of misfolded proteins, activates the unfolded protein response (UPR) to restore protein homeostasis. Dysregulated ER stress responses have emerged as critical modulators of cancer progression and immune escape, influencing the initiation, development and maintenance of antitumor immunity. The UPR is mediated by three principal sensors—PERK, IRE1α, and ATF6—each operating at distinct regulatory levels to coordinate translational reprogramming, RNA processing, and transcriptional reprogramming. Through these mechanisms, ER stress promotes malignant progression, tumor growth, and metastasis, while excessive activation can instead trigger cell death. Given this context-dependent duality, pharmacological targeting of the UPR has emerged as a promising anticancer strategy. For instance, IRE1α inhibitors block XBP1 splicing and RIDD-mediated immune escape, PERK inhibitors and ISR modulators reverse chemoresistance, ATF6-targeted strategies modulate ATF6-dependent tumor growth and treatment responses, and chemical chaperones exhibit both cytoprotective and antitumor effects depending on tumor context. 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.
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.
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
Summary Activating transcription factor 4 (ATF4) has emerged as a central mediator of cellular stress adaptation, exerting context-dependent and often opposing functions in cancer through the coordinated regulation of metabolism and tumor immunity. However, the mechanistic principles governing ATF4’s functional switch between tumor promotion and suppression remain incompletely defined, and the translational challenges of targeting this pleiotropic transcription factor have not been systematically evaluated. In this review, we dissect the molecular frameworks by which ATF4 integrates stress signals from the endoplasmic reticulum, oxidative stress, and nutrient deprivation to orchestrate metabolic reprogramming and immune evasion. We further critically assess the therapeutic landscape, including pharmacological selectivity, toxicity, and druggability challenges, all of which must be addressed to harness ATF4 as a precision target in oncology.
Zhiying Peng, Tong Xu, Z. Xia et al.· iScience· 0 citations
The tumor microenvironment (TME) is a complex ecosystem with harsh conditions, such as hypoxia, nutrient deprivation, metabolic acidosis and oxidative stress, that promote tumor progression and shape immune responses. In this environment, endoplasmic reticulum stress and the unfolded protein response are activated, with the transcription factor X-box binding protein 1 (XBP1) serving a key role. XBP1 not only maintains cell protein homeostasis, but also modulates the generation, metabolic adaptation and immunosuppressive function of myeloid-derived suppressor cells (MDSCs). The TME and tumor-derived factors, such as exosomes, remotely activate XBP1 in MDSCs, enhancing their survival and immunosuppressive capability by reprogramming lipid and glucose metabolism and upregulating the expression of arginase-1, inducible nitric oxide synthase, reactive oxygen species and immunosuppressive cytokines. The present review aimed to describe the TME stress-XBP1-MDSC-immunosuppression axis, its molecular mechanisms and the role of XBP1 in MDSC heterogeneity and plasticity. Targeting XBP1 may enhance the efficacy of existing therapies, particularly immune checkpoint blockade, by alleviating MDSC-mediated immunosuppression, offering a novel paradigm for understanding and reversing tumor immune escape.
Ziwei Chen, Jiaqi Wu, Wenxi Liu et al.· International Journal of Mol...· 0 citations
Endoplasmic reticulum stress (ERS) and the unfolded protein response (UPR) operate as central signaling hubs that integrate cellular homeostasis, adaptation, and fate determination. Dysregulation of this network constitutes a common pathogenic thread across cancer, metabolic syndromes, neurodegeneration, and inflammatory disorders. Although small molecule ERS modulators have validated the therapeutic relevance of this axis, their clinical translation remains constrained by intrinsic pharmacokinetic limitations, including poor solubility, off-tissue distribution, and an inability to synchronize drug action with the fluctuating dynamics of ERS. Nanotechnology is now catalyzing a paradigm shift by which engineered nanocarriers do not merely deliver ERS-targeting agents more efficiently; they unlock entirely new modalities of ERS intervention. By integrating stimuli-responsive motifs responsive to pH, reactive oxygen species, or enzymes, nanocarriers enable spatiotemporally programmable release that aligns therapeutic action with disease microenvironments. Through surface engineering and subcellular tropism, they achieve organelle-resolved ERS calibration, directing cargoes to the endoplasmic reticulum, mitochondria, or Golgi apparatus to modulate stress at its source. Beyond subcellular compartments, nanocarriers can also be tailored to target specific immune subsets, enabling precise modulation of ERS in dendritic cells, macrophages, and T lymphocytes. This emerging capability provides a means to reshape antigen presentation, inflammatory polarization, and effector functions, thereby linking ERS biology to cancer immunotherapy, autoimmune regulation, and infectious disease control. When integrated with epigenetic modulation, nanocarrier-mediated co-delivery of genetic and epigenetic agents offers a convergent strategy to simultaneously reprogram UPR signaling and correct epigenetic aberrations, thereby achieving superior therapeutic outcomes in ERS-driven diseases compared with single-modality approaches. This review systematically dissects nanocarrier-enabled strategies for ERS modulation, with emphasis on their architectural innovations in drug delivery, molecular logic of intervention, and therapeutic applications across major disease models. We also discuss current barriers to clinical translation and highlight emerging directions for extending ERS-targeted interventions toward broader pathological contexts.
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
