Synergistic Modulation of ER Stress and Insulin Potentiation Therapy for Enhanced Cancer Treatment

Cancer cells sustain rapid growth by reprogramming their metabolism to depend heavily on glycolysis, enhanced insulin signaling, and adaptive changes in the unfolded protein response (UPR). Insulin Potentiation Therapy (IPT) enhances the efficacy of chemotherapy by increasing insulin receptor expression, thereby improving the uptake of chemotherapeutic agents. Meanwhile, targeting endoplasmic reticulum (ER) stress disrupts the protein-folding machinery within cancer cells, steering them toward apoptosis. However, IPT faces several limitations, including limited clinical evidence, variable responses across tumor types, and concerns regarding safety and standardization. This review is the first to comprehensively examine the combined modulation of ER stress and IPT, highlighting novel clinical applications and presenting supporting evidence for this synergistic approach in cancer treatment. We compare the distinct metabolic features of cancer cells with those of normal cells and analyze how these differences contribute to tumor progression, the critical role of ER stress in cancer development, and the influence of insulin on cancer metabolism. In addition, we explore the potential synergy between IPT and ER stress modulation by delving into the mechanisms underlying IPT, the benefits of integrating ER stress modulation with IPT, and how insulin can modulate ER stress to improve therapeutic outcomes.