Mastering Immune Activation: Precision Targeting of ER Stress and STAT3 in Cancer Therapy

Tumor progression and therapeutic responsiveness are deeply influenced by the ways cancer cells adapt to stress, particularly within the endoplasmic reticulum (ER), and by how they engage immune-modulatory pathways. This thesis examines three interwoven aspects of these processes, with a focus on endoplasmic reticulum stress and the transcription factor Signal Transducer and Activator of Transcription 3 (STAT3). In hepatocellular carcinoma models, a combined approach of sorafenib treatment and STAT3 suppression intensifies ER stress, thereby triggering a robust pro-apoptotic response through the eIF2α/ATF4/CHOP axis. This heightened stress is further tied to enhanced anti-tumor immunity involving the cyclic GMP–AMP synthase (cGAS)–Stimulator of Interferon Genes (STING) pathway. A second study underscores the contribution of the Protein Kinase R-like ER Kinase (PERK)–CCAAT/Enhancer-Binding Protein δ (C/EBPδ) axis in breast cancer and melanoma cells, which fosters sustained chemokine secretion under ER stress and may shape a tumor-promoting immune environment. Finally, triple-negative breast cancers that harbor high levels of chromosomal instability, where cGAS–STING activation paradoxically drives interleukin-6 (IL-6)–STAT3 signaling to support tumor cell survival will be discussed. In these aneuploid contexts, blocking the IL-6 receptor (IL-6R) selectively undermines cancer viability, highlighting a dualistic role for cGAS–STING in either sustaining or suppressing tumors, depending on downstream effectors.