| Altered Response to Targeted Immunotherapy in Metastatic Breast Cancer: The Role of Molecular Signaling Networks |
| Paper ID : 1323-IGA |
| Authors |
|
Nazila Bahmaie *1, Maryam Mohammadi2, Pourandokht Farhangian3, Ali Bahadori4, Dina Eghbal Ghareh Tapeh5, Seyedeh Mona Aghamirzaei6, Mohammad Maroufi7, Parisa Abedi Elkhichi8, Ghazal Esfahani Maragheh9, Ali Zehtab Salehi10, Parya Karimpour11, Rezvan Tahmasbi9, Parisa Salmani Khormalou12, Maryam Madani Asl10, Pouya Paidar13, Melika Ansarin14, Nasim Mohammadi15, Mehrasa Nikandish16, Bahare Kasaei17, Mehrnaz Baneshi18, Maryam Sadat Jamadi19 1Department of Medical Biology, Faculty of Medicine, Ankara Yildirim Beyazit University (AYBU), 06800 Ankara, Turkey. 2Department of Microbiology, Faculty of Basic Medical Sciences, Tehran Medical Science Center (TeMS.C.), Islamic Azad University, Tehran, Iran. 3Department of Medical Genetics and Molecular Medicine, Faculty of Medicine, Zanjan University of Medical Sciences, Zanjan, Iran. 4Department of Medical Microbiology, Sarab Faculty of Medical Sciences, Sarab, East Azerbaijan, Iran. 5Department of Genetics, School of Basic Sciences and Advanced Technologies in Biology, University of Science and Culture, Tehran, Iran. 6College of Medical, Veterinary, and Life Sciences, University of Glasgow, Glasgow, United Kingdom. 7Department of Biology, Faculty of Basic Sciences, Urmia Center (Ur.C.), Islamic Azad University, Urmia, Iran. 8Infectious Diseases Research Center, Aja University of Medical Sciences, Tehran, Iran. 9Department of Animal Biology, Faculty of Natural Sciences, University of Tabriz, Tabriz, Iran. 10Department of Naturopathy, Faculty of Natural Medicine, Turkish International University of Technofest Institute of Technology (TITU), Turkey (Türkiye) Branch. 11Department of Biological Sciences, Faculty of Sciences, University of Kurdistan, Sanandaj, Kurdistan, Iran 12Department of Midwifery, Faculty of Nursing and Midwifery, Tabriz Medical Sciences Center (TaMS.C.), Islamic Azad University, Tabriz, East Azerbaijan, Iran. 13Department of Computer Engineering, Faculty of Engineering, Graduate School of Natural and Applied Sciences, Gazi University, Ankara, Turkey (Türkiye). 14Department of Obstetrics and Gynecology, Faculty of Medicine, Iran University of Medical Sciences (IUMS), Tehran, Iran. 15Department of Pharmacy, Faculty of Pharmacy, Kerman University of Medical Sciences (KUMS), Kerman, Iran 16Department of Pharmaceutical and Cancer Medicine, King's College London, London, United Kingdom. 17Birmingham University of Dubai, Dubai, United Arab Emirates. 18Department of Applied Sciences, University of Huddersfield, Huddersfield, United Kingdom 19Department of Obstetrics and Gynecology, Faculty of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran. |
| Abstract |
| Metastatic Breast Cancer (MBC) remains a major clinical challenge due to its high rate of mortality, heterogeneity, as well as a limited long-term response to current therapies. Hence, it seems that there is an imperative need to search for more efficient clinical procedures against MBC, through a deeper understanding on some common molecular immunopathophysiological pathways involved in the Tumor Microenvironment (TME) of MBC. Dysregulated signaling networks, including mutations in PI3K/AKT/m TOR, MAPK/ERK, HER2/EGFR, and JAK/STAT pathways, play a central role in fostering immune evasion (by reducing antigen presentation), impairing T-cell infiltration (by enhancing PD-L1 expression), modulating tumor-immune crosstalk (by affecting checkpoint blockade responsiveness), impairing cytotoxic immune activation (by disrupting interferon signaling), respectively. As direct consequences, tumor progression, recurrence, relapse, and therapeutic resistance are expected. Although targeted therapies such as HER2 inhibitors, CDK4/6 inhibitors, and PI3K inhibitors have improved optimized clinical outcomes for patients with MBC, both primary and acquired resistance frequently emerge through secondary mutations, pathway cross-talk (emerged as multiple primary tumors or syndromes or second primary malignancies), and metabolic or epigenetic reprogramming. Similarly, while immune checkpoint inhibitors have shown promise, particularly in triple-negative breast cancer, their efficacy is restricted by TME factors, variable PD-L1 expression, and immune escape mechanisms. Recent evidence suggests that rational combinations of targeted therapy and immunotherapy may overcome resistance by enhancing tumor immunogenicity and restoring anti-tumor immune responses. Identifying predictive molecular biomarkers and integrating multi-omics approaches will be essential to guide personalized treatment strategies. This review highlights the interplay between signaling cascades and therapeutic response in MBC, emphasizing the need for combinatorial and precision-based approaches to improve clinical outcomes. |
| Keywords |
| Metastatic Breast Cancer, Signaling Networks, Targeted Immunotherapy, Resistance, Molecular Biomarkers, Precision Medicine. |
| Status: Accepted |
