Abstract: G protein-coupled receptors (GPCRs), the largest family of transmembrane signal transducers in human genome, play pivotal regulatory roles in the initiation and progression of major diseases including cancer. Recent studies have shown that metabolitesensing GPCRs can specifically recognize and respond to various tumor-associated metabolites, thereby activating immunosuppressive signals, and further inducing tumor immune escape and drug resistance, rendering them frontier targets in the field of tumor immunotherapy. This review elucidates the mechanisms by which metabolite-sensing GPCRs represented by prostaglandin and adenosine receptors drive tumor immune escape. Meanwhile, it summarizes the key achievements in drug development and the latest clinical research progress targeting these two types of receptors, and conducts in-depth analysis of the opportunities and challenges faced by such targeting drugs in the process of clinical translation, so as to provide new perspectives and insights for the development of nextgeneration tumor immunotherapeutic agents.