Tumor exosomes impact functional hallmarks of cancer

Cancer-derived extracellular vesicles (EVs), particularly exosomes, transfer oncogenic proteins, metabolites and nucleic acids to both nearby and distant cells. These diverse bioactive molecules act synergistically to promote cancer progression by simultaneously modulating multiple signaling networks in recipient cells. By inducing coordinated and complex molecular reprogramming, exosomes provide tumors with a powerful mechanism to drive the diverse processes required for malignant growth, invasion, metastasis and immune modulation. This review integrates recent and landmark studies from primary studies of tumor exosomes and how they influence critical features of cancer as defined in the updated 2022 Hallmarks of Cancer framework. Tumour-derived exosomes not only drive proliferative signalling and metabolic rewiring, but also actively reprogram the stromal and immune compartments of the tumour microenvironment and condition distant tissues to form metastatic niches. In particular, we focus on hypoxia-driven exosome biology. The low-oxygen conditions that characterize most solid tumors enhances exosomal biogenesis and selectively enriches cargo with active molecules to promote angiogenesis, cancer cell survival, epithelial-mesenchymal transition, immune evasion and metastasis. The hypoxia-conditioned exosomes act as long-range carriers of stress-adaptation signals, extending the influence of the hostile tumour microenvironment to diverse cell types. Furthermore, we examine emerging roles for tumor-derived exosomes in modulating host-microbial interactions and influencing the efficacy of immune checkpoint inhibitors, highlighting vesicle-mediated communication between tumors, the immune system, and polymorphic microbiomes. We also explore the potential of targeting exosome-mediated pathways for therapeutic and diagnostic applications. By mapping recent experimental findings onto the updated hallmarks of cancer, this review integrates the central role of exosomes in malignant progression and highlights their potential as therapeutic targets in the clinic.