Although immune checkpoint blockade (ICB) has become the mainstay of treatment for advanced solid organ malignancies, success in revitalizing the host anticancer immune response remains limited. G-protein coupled receptors (GPCRs) are a broad family of cell-surface proteins that have been regarded as main players in regulating the immune system, namely by mediating the activity of T lymphocytes. Among the most novel immunoregulatory GPCRs include GPR171, lysophosphatidic acid receptors (LPARs), GPR68, cannabinoid receptor 2 (CB2), and prostaglandin E receptors, many of which have shown promise in mediating antitumor response via activation of cytotoxic T cells, inhibiting immunosuppressive lymphocytes, and facilitating immune cell infiltration within the tumor microenvironment across multiple types of cancers. This paper reviews our current understanding of some of the most novel GPCRs-their expression patterns, evolving roles within the immune system and cancer, potential therapeutic applications, and perspective for future investigation.