Decoding the crosstalk between ubiquitination and other post-translational modifications in cancer immunity: from mechanisms to clinical prospects.

The tumor microenvironment is dynamically regulated by complex post-translational modifications (PTMs), which play pivotal roles in cancer immunity. Ubiquitination, along with other PTMs such as phosphorylation, glycosylation, and acetylation, orchestrates immune checkpoint activity and immune cell function, shaping antitumor responses. In this review, we discuss the intricate crosstalk and regulatory mechanisms between ubiquitination and other PTMs in cancer immunity. Studies have revealed that the stability and function of immune checkpoint proteins, such as PD-L1, are dynamically regulated by synergistic or competitive modifications, which directly shape the tumor microenvironment's immunological characteristics. We highlight how PTMs regulate immune cell function (e.g., T cells, NK cells, and macrophages) and key signaling pathways (e.g., STAT, type I IFN, and NF-κB) in the TME. Furthermore, we summarize potential therapeutic strategies targeting these PTMs, including small-molecule inhibitors and novel technologies (e.g., PROTACs and cell-penetrating peptides), which offer insights into overcoming immunotherapy resistance and optimizing combination therapies. Future research should explore non-classical PTMs and leverage multi-omics approaches to refine precision immunotherapy strategies.