Water solubility and structural stability are key merits for proteins defined by the primary sequence and 3D-conformation. Their manipulation represents important aspects of the protein design field that relies on the accurate placement of amino acids and molecular interactions, guided by underlying physiochemical principles. Emulated designer proteins with well-defined properties both fuel the knowledge-base for more precise computational design models and are used in various biomedical and nanotechnological applications. The continuous developments in protein science, increasing computing power, new algorithms, and characterization techniques provide sophisticated toolkits for solubility design beyond guess work. In this review, we summarize recent advances in the protein design field with respect to water solubility and structural stability. After introducing fundamental design rules, we discuss the transmembrane protein solubilization and de novo transmembrane protein design. Traditional strategies to enhance protein solubility and structural stability are introduced. The designs of stable protein complexes and high-order assemblies are covered. Computational methodologies behind these endeavors, including structure prediction programs, machine learning algorithms, and specialty software dedicated to the evaluation of protein solubility and aggregation, are discussed. The findings and opportunities for Cryo-EM are presented. This review provides an overview of significant progress and prospects in accurate protein design for solubility and stability.

A2A receptors (A2AR), a typical GPCR with a high affinity for adenosine, was expressed in many immune cells, such as regulatory T cells, cytotoxic T cells, macrophages, etc. Adenosine binding to the A2AR receptor activates the typical G protein and triggers the cAMP/PKA/CREB pathway. The adenosine-A2AR pathway plays an important role in protecting normal organs and tissues from the autoimmune response of immune cells. However, many solid tumors hijack the adenosine-A2AR pathway by promoting adenosine accumulation. The activation of the A2AR pathway inhibited the immune response of immune cells and then promotes the immune escape of tumor cells in the tumor microenvironment. Recently, both animal experiments and clinical trials indicated that blocking the adenosine pathway can inhibit the progression of a variety of solid tumors. In addition, it is encouraging that A2AR blockade combined with CAR T cells therapy showed better anti-tumor efficacy. Therefore, this review will discuss the role of the adenosine-A2AR pathway in the tumor microenvironment and summarize recent advances of A2AR-cancer related studies.