Background: Cancer is characterized by unregulated cell proliferation, enabling it to invade and spread to different organs and tissues in the body. Cancer progression is intricately influenced by the complex dynamics within the tumor microenvironment (TME). The tumor microenvironment (TME) is a composite and dynamic network comprising cancer cells and various immune cells, including tumor-associated macrophages. Exosomes facilitate the cross-talk between different cancer cells and other cells. This review particularly focuses on exosomal proteins derived from different cancer cells in mounting the complex communication between cancer cells and macrophages within the tumor microenvironment. Most cancer-derived exosomal proteins polarize macrophages towards M2 phenotype, promoting cancer aggressiveness, while a few have role switching towards the M1 phenotype, inhibiting cancer proliferation, respectively. In this review, we summarize, for the first time, the dual impact of cancer cell-derived exosomal proteins on macrophage polarization and the associated signaling pathways, offering valuable insights for developing innovative therapeutic strategies against diverse cancer types. Conclusion: The exosomal proteins derived from different cancer cells can polarize macrophages into either classically activated M1 phenotype or alternatively activated M2 phenotype. This review provides insights and describes the role of different cancer cell-derived exosomal proteins and the associated signaling pathways that lead to macrophage polarization and further promote or inhibit cancer progression.

Dorzolamide (DZD), a Carbonic anhydrase (CA) inhibitor clinically used to lower intraocular pressure, exhibits anti-inflammatory effects owing to the drug’s ability to inhibit the TIR domain-containing adaptor protein (TIRAP)-mediated signaling in macrophages. Here, we investigated whether DZD intermediates also demonstrate any anti-inflammatory property like DZD but with a reduced inhibition of CA. We found that several intermediates of DZD show increased binding to TIRAP at the common interface of kinases, such as Protein kinase C-delta (PKCδ) and Bruton’s tyrosine kinase (BTK). Such binding results in a decreased activity of TIRAP, p38 (Mitogen-activating protein kinases) MAPK, and p65, which are essential for major inflammatory signaling pathways. Remarkably, the DZD intermediates were more potent than DZD in decreasing the mRNA expression levels of pro-inflammatory cytokines in LPS-stimulated RAW 264.7 cells. The DZD intermediates also exhibit a reduced binding energy to CA II and CA IV, highlighting their improved specificity as anti-inflammatory compounds with decreased unwanted biological effects. Furthermore, we validated the anti-inflammatory effect of the most potent DZD intermediate, DRZ V, in a model of mouse sepsis. DRZ V-treated septic mice exhibited improved survival compared to DZD-treated septic mice. Our data indicate that the tested DZD intermediates are more potent in dampening TIRAP-mediated inflammatory signaling as compared to DZD. Thus, DZD intermediates may be a promising option for developing novel anti-inflammatory therapeutics.