Ubiquitin signaling in tumor-associated macrophage reprogramming: mechanisms and therapeutic opportunities in cancers

Tumor-associated macrophages (TAMs) are key regulators of tumor progression and immune suppression within the tumor microenvironment (TME). Emerging evidence identifies ubiquitination, a dynamic post-translational modification that regulates protein stability, localization, and signaling activity, as a critical determinant of TAM function. Ubiquitin signaling orchestrates macrophage inflammatory responses, metabolic reprogramming, and tumor cell-immune cell crosstalk through coordinated actions of ubiquitin-activating enzymes, ubiquitin-conjugating enzymes, ubiquitin-protein ligases (E3s), and deubiquitinating enzymes (DUBs). Dysregulation of these ubiquitin networks fosters an immunosuppressive microenvironment, thereby promoting tumor growth, metastasis, and therapeutic resistance. In this review, we summarize recent advances in the role of ubiquitination in TAM biology, focusing on key E3 ubiquitin ligases and DUBs in TAM immunity. We further discuss emerging ubiquitin-dependent signaling pathways that integrate metabolic and inflammatory cues within TAMs. Finally, we highlight the therapeutic potential of targeting ubiquitination machinery to reprogram TAMs and remodel the TME. Collectively, this review provides a comprehensive framework for understanding ubiquitin-mediated regulation of TAM function and offers novel perspectives for developing ubiquitination-based cancer immunotherapies.