Analysis of Immune Resistance Mechanisms in TNBC: Dual Effects Inside and Outside the Tumor

Abstract

Triple-negative breast cancer (TNBC) is a unique subtype of breast cancer characterized by the lack of expression of the estrogen receptor, progesterone receptor, and human epidermal growth factor receptor 2. TNBC exhibits a high degree of aggressiveness, metastatic potential, and a poor prognosis. Despite the limited success of conventional treatments, immune checkpoint inhibitors (ICIs) have emerged as promising therapeutics for TNBC. Therefore, understanding the mechanisms underlying innate and acquired resistance to ICIs in TNBC is essential. Numerous studies suggest that intrinsic and extrinsic factors significantly contribute to the development of ICI resistance in TNBC. Intrinsic resistance may result from alterations in tumor-intrinsic signaling pathways, such as dysregulation of interferon (IFN) signaling or other signaling pathways. In contrast, extratumoral mechanisms may develop due to alterations in the tumor microenvironment, changes in T cell-related factors or adaptations within the immune system itself. In this paper, we endeavor to elucidate the underlying mechanisms of immune resistance by systematically examining immune mechanisms, the present state of immunotherapy, and the processes of immune resistance. Nonetheless, enhancing our understanding of the mechanisms underlying intratumoral and extratumoral resistance to ICIs in TNBC is crucial for optimizing patient outcomes in this challenging disease. Persistent efforts to identify novel targets for combination therapies, biomarkers that can predict the response to immunotherapy, and resistance mechanisms will be instrumental in achieving this objective.