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

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.