The intricate dance between endoplasmic reticulum stress (ERS) and programmed cell death within the tumor microenvironment (TME) is reshaping our understanding of cancer biology and treatment. Tumors harness ERS signaling pathways in diverse and dynamic ways, influencing cancer cell fate, immune interactions, and therapy resistance across multiple malignancies. Recent advances unravel how ERS orchestrates both death and survival, offering fresh avenues for therapeutic innovation.
In breast cancer, distinct subtypes display notable heterogeneity in ERS response. Estrogen receptor-positive (ER+) tumors often tolerate moderate ERS activation, which facilitates cellular adaptation. However, persistent ERS provokes apoptosis through intricate mitochondria-endoplasmic reticulum calcium signaling and reactive oxygen species (ROS) accumulation. Conversely, triple-negative breast cancers endure heightened baseline ERS, making them susceptible yet simultaneously adept at developing resistance via anti-apoptotic proteins such as FLIP. This dualistic nature exemplifies the balancing act cancer cells perform between survival and death, underscoring the challenge of exploiting ERS pathways therapeutically.
Within the complex tumor microenvironment, stressors like hypoxia, acidity, and nutrient scarcity act as relentless triggers for the unfolded protein response (UPR), perpetuating ERS signaling. ERS reciprocally remodels the microenvironment, simultaneously enhancing anti-tumor immunity by inducing immunogenic cell death (ICD) through modalities such as calreticulin exposition and HMGB1 release, while also promoting immunosuppression via mechanisms including PD-L1 glycosylation. Notably, ERS-mediated exosomal microRNAs, like miR-27a-3p, modulate macrophage immune checkpoint expression via molecular cascades, revealing sophisticated tumor immune escape strategies embedded within ERS signaling frameworks.
Colorectal cancer’s interplay between ERS and various cell death modalities underscores a nuanced regulatory landscape. The ferroptosis inducer RSL3 activates all UPR arms, with the PERK pathway dampening ferroptosis by modulating transcriptional regulation of critical cystine-glutamate antiporter components. This interplay suggests that modulating ERS pathways could overcome traditional apoptosis resistance, opening new therapeutic horizons. Moreover, dual induction of ferroptosis and ICD by agents like macrocarpal I enhances the efficacy of immune checkpoint blockade, highlighting the benefit of temporally calibrated ERS manipulation.
Hepatocellular carcinoma (HCC) demonstrates how ERS signaling pathways intertwine with diverse cell death forms to dictate tumor behavior and therapeutic outcome. Natural compounds, such as Icaritin and Fisetin, leverage ERS activation to induce mitochondrial dysfunction and calcium disruption, amplifying apoptotic pathways. Under therapeutic stress, ERS-induced autophagy serves as a protective shield against apoptosis, contributing to sorafenib resistance. Interventions that modulate this crosstalk, including melatonin’s inhibition of protective autophagy, reinstate drug sensitivity. Furthermore, ERS elements also govern metastatic potential by fostering anoikis resistance, indicating these pathways’ role extends beyond cell death into tumor dissemination.
Glioblastoma multiforme (GBM) epitomizes the challenges of therapy resistance linked to ERS/UPR dysregulation. Compounds such as sulforaphane induce ATF4–CHOP mediated apoptosis, whereas proteasome inhibitors, like marizomib, trigger caspase-dependent cell death independent of ROS or autophagy pathways. Intriguingly, remdesivir exhibits superior antitumor efficacy via PERK-orchestrated UPR, hinting at repurposed antiviral agents’ potential in oncology. The heterogenous ERS response in therapy-resistant GBM subtypes highlights the complexity of the tumor’s adaptive machinery and emphasizes the need for combination strategies targeting multiple ERS nodes.
Lung cancer progression and immune evasion are intimately linked with ERS-induced modulation of the tumor milieu. The oxidoreductase ERO1A shapes immunosuppressive environments by balancing IRE1α and PERK pathways and its inhibition potentiates PD-1 blockade responses. Other modulators like Derlin-3 drive macrophage polarization, reinforcing immune escape. Photodynamic therapies exploit ROS to instigate ERS and DNA damage, bolstering tumor immunogenicity. Furthermore, ERS-related gene signatures serve as prognostic indicators, with high-risk groups exhibiting blunted immune infiltration and attenuated treatment responses, illuminating the translational relevance of ERS biomarkers.
In pancreatic ductal adenocarcinoma (PDAC), ERS is a double-edged sword that propels tumor progression and resistance. Single-cell analyses have spotlighted tumor-associated neutrophil subsets with glycolytic profiles governed by ERS-associated transcription factors, fostering immunosuppression via chemokine secretion and checkpoint regulation. The molecular crosstalk where RUNX1 activates BiP/PERK/eIF2α signaling reinforces chemoresistance, which can be reversed pharmacologically. Nanotechnology-based delivery systems simultaneously targeting ERS pathways and immune checkpoints exemplify the frontiers of therapeutic innovation in this notoriously resistive cancer type.
Natural products across cancer types consistently emerge as potent ERS modulators to induce tumor cell death. Tocotrienols and oleandrin in breast cancer, curcumin and gambogenic acid in colorectal cancer, and secoemestrin C in PDAC exemplify the therapeutic potential harnessed from bioactive compounds targeting ERS-death axes. These agents engender ERS-mediated apoptosis through canonical pathways such as PERK-eIF2α-ATF4-CHOP or induce irreversible proteostasis collapse, thus overcoming conventional drug resistance mechanisms.
Therapeutic resistance often pivots on dynamic ERS responses where the equilibrium between death and survival signals is delicately tuned. For instance, sorafenib’s induction of protective autophagy via the PERK-ATF4-Beclin1 cascade in HCC demonstrates how a cytoprotective mechanism can complicate treatment outcomes. Agents that disrupt these survival cues restore apoptotic sensitivity, a principle echoed across tumor models. Similarly, in GBM, proteasomal activity modulates ERS and autophagy interplay, influencing temozolomide resistance, and targeting these pathways enhances therapeutic efficacy.
The tumor microenvironment reprogrammed by ERS influences metastatic progression and immune landscape remodeling. In HCC, ERS-adaptive proteins enhance anoikis resistance, promoting metastasis correlating with clinical metrics such as tumor size and stage. ERS-driven immunosuppressive signaling axes, like MIF/CD74+CXCR4, underscore how tumors manipulate local immunity to their advantage. Interventions that modulate ERS can shift this balance, restoring immune surveillance and dampening metastatic propensity.
Emerging therapies targeting the ERS machinery demonstrate profound potential in enhancing cancer treatment. Combinations such as PERK agonists with taxanes or proteasome inhibitors paired with ERS inhibitors unleash synergistic apoptotic responses. Novel targeted agents, including UBA1 and GRP78 inhibitors, induce irreversible UPR tipping cancer cells beyond their adaptive capacity. Nanoformulations augment delivery and efficacy of ERS modulators, underscoring the importance of technological advances in translating these molecular insights into clinical reality.
Metabolic reprogramming intimately intersects with ERS regulation, bridging cellular stress and tumor survival. Lung and pancreatic cancers exhibit metabolic alterations that integrate with ERS signaling to confer adaptive advantages. The PERK pathway, via modulators like BZW1 and PPARγ ligands, orchestrates glycolysis and ROS balance, influencing cell fate decisions under metabolic duress. Targeting these metabolic-ERS nodes disrupts tumor resilience, providing a multifaceted approach to combat resistant malignancies.
Within glioblastoma, the tumor’s subpopulation heterogeneity reveals distinct ERS dependencies that correlate with treatment sensitivity and recurrence. Strategies disrupting protein ubiquitination and folding, such as the UBA1 inhibitor TAK-243, combined with GRP78 antagonists, demonstrate remarkable potential in overcoming GBM robustness. Moreover, metabolic interventions harnessing ERS-mitochondrial crosstalk exploit vulnerabilities in glioma stem cells, emphasizing the crucial role of integrated stress responses in tumor eradication.
The immunogenic potential of ERS-induced cell death is increasingly recognized as a critical component in orchestrating effective antitumor immunity. Agents that trigger ICD, including several natural and synthetic compounds, not only kill cancer cells but also prime immune responses by exposing damage-associated molecular patterns. This dual function advocates for ERS-targeted therapies in combination with immunotherapies, aiming to dismantle immune evasion mechanisms entrenched within tumor microenvironments across cancer types.
The intricate nexus between ERS, programmed cell death, and the tumor microenvironment emerges as a fertile landscape for transformative cancer therapies. As the molecular choreography underlying ERS signaling pathways continues to unfold, it paves the way for innovative interventions that can finely tune this balance, circumvent resistance, and mobilize anti-tumor immunity. The future of oncology lies in decoding and manipulating this multifaceted axis to achieve durable clinical successes.
Subject of Research: Endoplasmic reticulum stress-mediated programmed cell death in the tumor microenvironment
Article Title: Endoplasmic reticulum stress-mediated programmed cell death in the tumor microenvironment
Article References:
Chai, H., Hu, Q., Yao, S. et al. Endoplasmic reticulum stress-mediated programmed cell death in the tumor microenvironment. Cell Death Discov. 11, 559 (2025). https://doi.org/10.1038/s41420-025-02862-6
Image Credits: AI Generated
DOI: 17 December 2025
Tags: breast cancer ER stress responsescancer therapy resistance mechanismsendoplasmic reticulum stress in cancerER stress and immune interactionsestrogen receptor-positive tumor adaptationhypoxia and cancer cell survivalimmunogenic cell death triggersprogrammed cell death mechanismstherapeutic implications of ER stresstriple-negative breast cancer resistancetumor microenvironment and cell deathunfolded protein response in tumors
