Overcoming immunotherapy resistance in breast cancer: a novel strategy by targeting the integrated stress response

Immunotherapy resistance remains a major obstacle in treating breast cancer, particularly aggressive subtypes like triple-negative breast cancer (TNBC). This review delineates the pivotal role of the Integrated Stress Response (ISR) as a central metabolic-immune regulator driving this resistance. The ISR is activated in the tumor microenvironment (TME) by diverse stressors—including hypoxia, nutrient scarcity, and ER stress—via four upstream kinases (PERK (PKR-like ER kinase), GCN2, PKR, HRI). These kinases converge to phosphorylate eukaryotic initiation factor 2α (eIF2α), leading to the selective translation and robust activation of the transcription factor ATF4. The ensuing ATF4-driven program fosters an immunosuppressive TME through multifaceted mechanisms: tumor-intrinsic upregulation of PD-L1, secretion of immunosuppressive exosomes, metabolic reprogramming that depletes critical amino acids, and direct impairment of T cell function and antigen presentation. Concurrently, ISR activation in immune cells—such as myeloid-derived suppressor cells (MDSCs) and dendritic cells—further dampens antitumor immunity. Targeting the ISR with small-molecule inhibitors (PERK or GCN2 inhibitors, ISRIB) or repurposed agents (metformin) demonstrates compelling preclinical efficacy in reversing immunosuppression and synergizing with immune checkpoint inhibitors. Biomarker-driven strategies, including ISR gene signatures and p-eIF2α immunohistochemistry, offer promising avenues for patient stratification. Thus, pharmacological targeting of the ISR represents a strategically viable approach to reprogram the immunosuppressive TME and overcome immunotherapy resistance in breast cancer, warranting urgent clinical investigation.