Open Access

REVIEW

Igniting the Tumor: Targeting Mitochondrial Stress to Prime Breast Cancer for Immunotherapy

Hung-Yu Lin^1,2,†, Hsing-Ju Wu^2,3,†, Pei-Yi Chu^1,4,5,*

1 Department of Post-Baccalaureate Medicine, College of Medicine, National Chung Hsing University, Taichung 402, Taiwan
2 Research Assistant Center, Show Chwan Memorial Hospital, Changhua 500, Taiwan
3 Department of Nursing, Jenteh Junior College of Medicine, Nursing and Management, Miaoli 356, Taiwan
4 Department of Pathology, Show Chwan Memorial Hospital, Changhua 500, Taiwan
5 National Institute of Cancer Research, National Health Research Institutes, Tainan 704, Taiwan † These authors contributed equally to this work

* Corresponding Author: Pei-Yi Chu,

European Cytokine Network 2025, 36(3), 24-37. https://doi.org/10.1684/ecn.2025.0504

Accepted 04 January 2026;

Abstract

Immunotherapy has demonstrated limited efficacy in immunologically “cold” breast cancers characterized by absent T-cell infiltration and inadequate interferon signaling. The purpose of this work is to propose and articulate a mechanistic and therapeutic framework in which mitochondrial stress is deliberately harnessed to convert immunologically “cold” breast tumors into “hot,” T cell–inflamed, immunotherapy-responsive lesions. This review synthesizes emerging evidence positioning mitochondrial stress as a strategic lever to transform these immune-excluded tumors into inflamed, therapy-responsive lesions. We examine how mitochondrial dysfunction triggers cytosolic release of mitochondrial DNA (mtDNA), a potent damage-associated molecular pattern that activates the cGAS-STING pathway, initiating type I interferon responses and secretion of T-cell-recruiting chemokines such as CCL5 and CXCL10. This axis functions as a “double-edged sword”—while acute activation converts “cold” tumors into “hot” immune-responsive states, chronic engagement drives immunosuppressive cytokine networks and therapeutic resistance, with outcomes varying across breast cancer subtypes. We explore six combination therapeutic strategies: mitochondrial poisons, radiotherapy/chemotherapy, PARP/ATR inhibitors, metabolic reprogramming agents, mitochondrial quality control modulators, and localized mitochondrial stress induction, each paired with immune checkpoint blockade. The review emphasizes “controlled ignition” as a paradigm whereby precisely dosed mitochondrial stress amplifies tumor antigenicity and favorable cytokine landscapes while avoiding chronic immunosuppression. Cytokine networks emerge as both integrators and therapeutic targets of mitochondrial-immune crosstalk. Future advances require mapping subtype-specific thresholds, developing tumor-restricted delivery systems, and implementing biomarker-guided trials to safely harness mitochondrial stress, potentially redefining these organelles as programmable immunological adjuvants in breast cancer therapy.

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Keywords

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