Stress-Response Pathways in Cancer Progression and Therapy Resistance: From ER Stress to DNA Damage Signaling

Cancer cells evolve under constant pressure from oncogene activation, hypoxia, nutrient limitation, immune surveillance, and therapeutic exposure. These stressors activate tightly regulated stress-response networks that can paradoxically suppress early tumorigenesis while later enabling tumor adaptation, metastatic competence, and resistance to therapy. Among the most consequential of these networks are endoplasmic reticulum (ER) stress signaling and the unfolded protein response (UPR), the integrated stress response (ISR), redox and metabolic stress programs, and DNA damage response (DDR) pathways that sense and repair genotoxic lesions and replication stress.

This Research Topic will explore how stress-response pathways are rewired across cancer types and disease stages, and how their crosstalk shapes cell fate decisions—apoptosis, senescence, autophagy, dormancy, and stem-like persistence—under both intrinsic and treatment-induced stress. We are particularly interested in mechanistic links between proteostasis disruption (e.g., PERK–eIF2α–ATF4/CHOP, IRE1–XBP1 and RIDD, ATF6 signaling), mitochondrial dysfunction, oxidative stress, and canonical DDR signaling (e.g., ATM/ATR, CHK1/CHK2, p53 axis, homologous recombination and non-homologous end joining), as well as emerging interfaces such as replication fork protection, chromatin remodeling, and inflammatory DNA sensing pathways (including micronuclei formation and cGAS–STING activation).

A major focus is therapy resistance. ER stress and DDR remodeling can promote survival under chemotherapy, radiotherapy, targeted therapies, and immunotherapies by enhancing adaptive translation programs, rewiring metabolism, increasing drug efflux, sustaining pro-survival autophagy, and facilitating efficient DNA repair or tolerance of DNA lesions. Conversely, these same pathways create actionable liabilities: proteostasis overload, dependence on specific repair nodes, stress-induced epigenetic states, and immunogenic consequences of unresolved damage. Understanding when stress signaling is protective versus targetable—and in which molecular contexts—remains a central challenge for precision oncology.

We welcome contributions that clarify stress-response circuitry in tumors and the tumor microenvironment, identify predictive biomarkers of stress pathway engagement, and nominate rational combination strategies to overcome resistance. Studies spanning molecular mechanisms, functional genomics, multi-omics profiling, advanced model systems, and translational/clinical datasets are encouraged, especially when they connect pathway activity to therapeutic response, metastatic progression, or immune modulation.

Potential themes include but are not limited to:

• ER stress/UPR and ISR as drivers of plasticity, dormancy, and stemness
• Replication stress, fork stability, and adaptive DNA repair in resistant states
• Autophagy, proteostasis, and metabolic rewiring under treatment pressure
• DDR–immune crosstalk, inflammatory signaling, and immunotherapy response
• Biomarkers and therapeutic targeting of stress dependencies (single-agent or combinations)
• Evolutionary Dynamics of Stress Signaling under Therapeutic Pressure
• Stress-Induced Epigenetic Reprogramming in Cancer Evolution
• Stress Signaling in the Tumor Microenvironment (TME)
• Mitochondrial Stress and Metabolic flexibility in Therapy resistance




Please note: Manuscripts consisting solely of bioinformatics, computational analysis, or predictions of public databases which are not accompanied by validation (independent clinical or patient cohort, or biological validation in vitro or in vivo, which are not based on public databases) are not suitable for publication in this journal.

Article types and fees

This Research Topic accepts the following article types, unless otherwise specified in the Research Topic description:

• Brief Research Report
• Case Report
• Clinical Trial
• Editorial
• FAIR² Data
• General Commentary
• Hypothesis and Theory
• Methods
• Mini Review
• ... View all formats

Articles that are accepted for publication by our external editors following rigorous peer review incur a publishing fee charged to Authors, institutions, or funders.

Article types

This Research Topic accepts the following article types, unless otherwise specified in the Research Topic description:

• Brief Research Report
• Case Report
• Clinical Trial
• Editorial
• FAIR² Data
• General Commentary
• Hypothesis and Theory
• Methods
• Mini Review
• Opinion
• Original Research
• Perspective
• Review
• Systematic Review
• Technology and Code

Keywords: ER stress and UPR, Integrated stress response, DNA damage response, Therapy resistance, Replication stress, Cancer cell plasticity, Tumor microenvironment

Important note: All contributions to this Research Topic must be within the scope of the section and journal to which they are submitted, as defined in their mission statements. Frontiers reserves the right to guide an out-of-scope manuscript to a more suitable section or journal at any stage of peer review.