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.