Abstract Colorectal cancer (CRC) is one of the deadliest cancer types and is characterized by a complex tumor microenvironment (TME), which includes cancer and immune cells engaging in intricate signaling crosstalk. TME is dependent on the CRC stage and contributes to cancer aggressiveness and therapy resistance. It has been established that tumor-associated immune cells can support cancer progression. However, the underlying mechanisms are not fully elucidated. Here, we provide evidence that communication between CRC and immune cells, particularly tumor-associated macrophages (TAMs), occurs through the release of soluble factors and extracellular vesicles (EVs), such as exosomes. Our study reveals that TAMs initially recognize exosomes as foreign entities, triggering a pro-inflammatory response. Over time, however, the contents of these phagocytosed exosomes reprogram the TAMs into an anti-inflammatory, tumor-supportive phenotype. Our data indicate that such a phenotypic transition in CRC TAMs is primarily triggered by the activation of the NF-kB transcription factor, and that inhibiting NF-kB signaling may significantly decrease the tumor-supportive functions of TAMs in CRC. Thus, pharmacologically slowing the transition of CRC TAMs from pro-inflammatory to tumor-supportive states may be a promising strategy to reduce cancer aggressiveness.
Wadhonkar et al. (Thu,) studied this question.