Protein serine/threonine phosphatases in tumor microenvironment: a vital player and a promising therapeutic target

The tumor microenvironment (TME) is involved in cancer initiation and progression. With advances in the TME field, numerous therapeutic approaches, such as antiangiogenic treatment and immune checkpoint inhibitors, have been inspired and developed. Nevertheless, the sophisticated regulatory effects on the biological balance of the TME remain unclear. Decoding the pathological features of the TME is urgently needed to understand the tumor ecosystem and develop novel antitumor treatments. Protein serine/threonine phosphatases (PSPs) are responsible for inverse protein phosphorylation processes. Aberrant expression and dysfunction of PSPs disturb cellular homeostasis, reprogram metabolic processes and reshape the immune landscape, thereby contributing to cancer progression. Some therapeutic implications, such as the use of PSPs as targets, have drawn the attention of researchers and clinicians. To date, the effects of PSP inhibitors are less satisfactory in real-world practice. With breakthroughs in sequencing technologies, scientists can decipher TME investigations via multiomics and higher resolution. These benefits provide an opportunity to explore the TME in a more comprehensive manner and inspire more findings concerning PSPs in the TME. The current review starts by introducing the canonical knowledge of PSPs, including their members, structures and posttranslational modifications for activities. We then summarize the functions of PSPs in regulating cellular homeostasis. In particular, we specified the up-to-date roles of PSPs in modulating the immune microenvironment, adopting hypoxia, reprogramming metabolic processes, and responding to extracellular matrix remodeling. Finally, we introduce preclinical PSP inhibitors with translational value and conclude with clinical trials of PSP inhibitors for cancer treatment.