Immune cell-derived exosomes in the tumor microenvironment: mechanisms of immune evasion and emerging therapeutic strategies in cancer immunotherapy

Abstract

Tumor-released exosomes have emerged from the shadows of “cellular dust” to be recognized as pivotal mediators of intercellular communication within the tumor microenvironment (TME). These nano-sized vesicles (30–150 nm) carry a complex cargo of proteins, lipids, and nucleic acids that profoundly reshape anti-tumor immunity. This review comprehensively examines the dualistic nature of immune cell-derived exosomes in cancer progression, with particular focus on exosomes originating from B lymphoma cells, T lymphocytes, natural killer (NK) cells, and myeloid-derived suppressor cell lineages including tumor-associated macrophages (TAMs), mast cells, and neutrophils. We delineate the mechanistic pathways through which these exosomes disrupt the cancer immunity cycle suppressing CD8+ T cell activation via PD-L1/PD-1 engagement, inducing lymphocyte apoptosis through FasL and TRAIL, promoting regulatory T cell expansion, polarizing macrophages toward the M2 immunosuppressive phenotype, and establishing pre-metastatic niches through MMP-mediated extracellular matrix remodeling. The molecular machinery governing exosome biogenesis including ESCRT-dependent and ceramide-mediated pathways is critically reviewed, alongside the selective packaging mechanisms that concentrate immunosuppressive miRNAs (miR-155, miR-21, miR-23a, miR-223) into exosomal compartments. Importantly, we highlight the emerging therapeutic premises targeting these vesicles: pharmacological inhibition of exosome secretion (GW4869, Rab27a knockdown), checkpoint blockade reversing exosomal PD-L1-mediated T cell exhaustion, and the engineering of immunostimulatory exosomes as cell-free cancer vaccines establishing exosomes not merely as biomarkers of disease progression but as actionable therapeutic targets. The clinical translation of exosome-based diagnostics including liquid biopsy platforms detecting circulating tumor-derived exosomes and therapeutics that include engineered exosomes delivering immunomodulatory cargo represents a frontier in precision cancer immunotherapy.