ABSTRACT Recent advances in checkpoint blockade immunotherapy (CBI) inhibiting programmed death-1 (PD-1) and cytotoxic T-lymphocyte antigen-4 (CTLA-4) have revolutionized cancer treatment. However, the limited response rates in most cancers suggest that new approaches and targets are clearly needed to fully elucidate the underlying biology of dysfunctional and exhausted CD8 T cells in cancer and achieve durable responses (cure). G-protein coupled receptors (GPCRs) are the most intensively studied drug targets since they play key roles in many physiological processes, and they have remained longstanding favorable pharmacological targets. Here, we plan to first use novel computational approaches analyzing multiple single cell RNAseq databases to deconvolute T cell heterogeneity in order to generate a transcriptomic GPCR signature for tumor infiltrating T cells. Preliminary data shows an upregulation of prostaglandin receptors, EP2 and EP4, on exhausted T cells, suggesting that these GPCRs that are coupled to the G protein Gs, and their downstream signaling cascades may be dampening anti-tumor cytotoxicity of CD8 T cells, leading to exhaustion. We hypothesize that activation of EP2 and EP4 on CD8 T cells and the subsequent Gs signaling leads to decreased cytotoxic and migratory activity that nullifies the effectiveness of PD-1 and CTLA-4 blockade. Put together, EP2 and EP4 may represent promising candidates as immune checkpoints that can be targeted in combination with CBI as part of novel multimodality precision immunotherapy approach to reactivate the immune system to destroy tumors.