From intercellular communication to therapeutic delivery: Mechanistic perspectives of cancer exosomes.
Exosomes, enriched with cancer-specific nucleic acids and proteins, have emerged as key intercellular communicators for orchestrating a tripartite axis of the tumor microenvironment (TME). They contribute significantly to tumor progression, particularly through their involvement in drug resistance, immune suppression, and metastasis. Recently, extensive research has mapped isolated functions to integrated perspective on how exosomal cargo mediates the complex crosstalk between these three important avenues of tumor survival. This begins by outlining the fundamental mechanisms of exosome biogenesis, cargo sorting and release that are frequently hijacked by cancer cells. This review then examines the exosome-mediated transfer of drug efflux pumps, non-coding RNAs, and metabolic enzymes from drug-resistant tumor cells to drug-sensitive cells. Subsequently, this review explore how tumor derived exosomes influence the premetastatic niche to support angiogenesis, including the horizontal transfer of key cytokines and growth factors. Additionally, this review details the role of tumor derived exosomes in shaping an immunosuppressive TME, especially their capacity to modulate T-cell function, polarize myeloid cells, and influence immune checkpoint signalling. Finally , we discuss emerging therapeutic strategies aimed at intercepting or reprogramming exosomal cargo to potentially prevent metastasis, sensitize tumor to therapeutics , and counteract immune evasion. By shifting the focus from isolated mechanisms to the interconnected roles of exosomes, this review aims to inform the rational design of next-generation exosome targeted and exosome based cancer therapeutics.