Immunomodulation of the Breast Cancer Microenvironment by Tumor-Derived Exosomes: Implications for Immunotherapy

Exosomes are 30-150 nm extracellular vesicles released by nearly all cells, including tumor cells. Cancer cell-derived exosomes carry various molecular contents - proteins, mRNAs, microRNAs- that are transferred to recipient cells, contributing to cancer development, angiogenesis, metastasis, and immune evasion. Breast cancer-derived exosomes (BEXs) express multiple immunomodulatory molecules, particularly the ectoenzymes CD39 and CD73, which catalyze the conversion of adenosine triphosphate (ATP) into adenosine. Adenosine then binds its receptors (ADORs) to transmit immunosuppressive signals. BEXs also express immune checkpoint molecules such as programmed death ligand 1 (PD-L1), CD200, and CD47 that suppress immune surveillance through interaction with programmed cell death protein 1 (PD-1), CD200R, and signal-regulatory protein alpha (SIRPα), respectively. Notably, PD-L1 appears to be more enriched on exosomes than on tumor cell surfaces, underscoring the pivotal role of BEXs in immune regulation. Given their influence on several hallmarks of cancer, BEXs are promising candidates for future diagnostic and therapeutic strategies, particularly in immunotherapy.