Targeting estrogen-related receptors to mitigate tumor resistance: A comprehensive approach to bridging cellular energy metabolism

The war between humanity and malignant tumors has been ongoing, with continuous advancements in classic chemotherapy and radiotherapy regimens, targeted drugs, endocrine therapy, and immunotherapy. However, tumor cells can develop primary or secondary resistance to these treatment options, making the issue of tumor resistance a major factor affecting patient prognosis and leading to recurrence. Estrogen-related receptors (ERRs) are members of the nuclear receptor superfamily, primarily involved in regulating glucose, lipid, and amino acid metabolism, serving as a central hub for intracellular energy metabolism. ERRs not only mediate insulin resistance but also participate in the mechanisms of drug resistance in various tumors, including breast cancer, osteosarcoma, endometrial cancer, lung cancer, and liver cancer, and even mediate resistance to radiation and immunotherapy. They mainly resist tumor treatment methods through metabolic reprogramming within cells, affecting mitochondrial energy metabolism, regulating metabolites such as cholesterol, glutamine, and lactate, or other signaling pathways, or by influencing the immune microenvironment. ERRs are promising targets for addressing the dilemma of tumor resistance. Currently, electrochemical luminescence biosensors for detecting ERRα in bodily fluids have been developed, making large-scale, low-cost detection of ERRα possible. Additionally, targeted inhibitors of ERRs have shown significant effects in suppressing cancer cell proliferation and reversing tumor resistance. This article reviews the research progress of ERRs in tumor resistance, providing important references for developing more effective anti-tumor treatment strategies.