The molecular language: decoding exosomal cargoes in macrophage-gastric cancer dialogue

Exosomes mediate a two-way signaling between gastric cancer (GC) cells and macrophages in the tumor microenvironment (TME) and have significant effects on tumor progression, immune suppression, and treatment outcomes. This paper will bring together existing literature on the vesicular cargo of macrophage-derived and GC-derived exosomes, such as non-coding RNAs (ncRNAs), and proteins, and their contribution to the re-polarization of macrophages, as well as the behavior of GC cells. The cargo contained in macrophage-derived exosomes biases signaling pathways associated with macrophage polarization, tumor-promoting phenotype, and helping GC proliferation, invasion, metastasis, and chemoresistance. Conversely, macrophage exosomal messages may complement anti-tumor immunity through the regulation of PD-L1 and augmentation of T cells. The exosomes of GC also remodel the macrophage phenotype in favor of immunosuppression by delivering cargoes, facilitating metabolic reprogramming, and tumor-associated macrophages (TAMs) polarization. This crosstalk is generalized to more widespread tumor stroma interactions, which involve cancer-associated fibroblasts (CAFs) and angiogenesis. The resulting therapeutic implications are engineered exosomes and cargo-modified vesicles to tip the balance towards anti-tumor immunity and overcome chemoresistance, where a high efficiency of loading and precision of targeting remain problematic, and the translation of preclinical research findings to the clinic.