1. Introduction

G protein-coupled receptors (GPCRs) are the largest and most diverse group of membrane receptors in eukaryotes (Grisshammer, 2017). The common structure of GPCRs consists of an extracellular N terminus, seven alpha-helical transmembrane domains (TM1-7) connected by three intracellular loops and three extracellular loops, and an intracellular C terminus (Baldwin, Schertler, & Unger, 1997). With this structure, GPCRs can translate extracellular stimuli into an intracellular response, mainly through heterotrimeric G proteins consisting of α, β, and γ sub-units. G proteins interact with other proteins, which activate a diverse array of downstream signaling pathways (Fredriksson, Lagerström, Lundin, & Schiöth, 2003). As such, GPCRs play important roles in the physiology of all major peripheral organ systems, and dysregulation of GPCRs are associated with various human diseases including type 2 diabetes (Hua Li et al. , 2013), Alzheimer’s disease (Nickols & Conn, 2014), hypertension (G. C. Sun et al. , 2015), heart failure (Cannavo, Liccardo, & Koch, 2013), and cancer (Young, Waitches, Birchmeier, Fasano, & Wigler, 1986). Therefore, GPCRs have received significant attention in drug discovery, and are targeted by nearly 34% of all FDA approved drugs{Hauser, 2017 #177} (Hauser, Attwood, Rask-Andersen, Schiöth, & Gloriam, 2017){Hauser, 2017 #177}. Over the past decades, GPCR-related signaling cascades have been linked to critical cellular processes such as proliferation, angiogenesis, and immune responses, all of which are pivotal in tumorigenesis and metastasis (Wu et al. , 2019). Moreover, abnormal expression and function of GPCRs have been identified in various cancer types, both in cancer cells and cancer-associated immune cells, presenting these receptors as potential biomarkers for cancer diagnosis and prognosis (Chaudhary & Kim, 2021; P. A. Insel et al. , 2018). However, current use of drugs targeting GPCRs in cancer therapy remains limited, with only a few in clinic (Table 1) and more in clinical trials, which have been summarized by Usman and others (Usman, Khawer, Rafique, Naz, & Saleem, 2020). Investigation of GPCRs as anti-cancer drug targets features various receptors and an array of small molecules and antibodies, exhibiting potential in different cancer types including prostate cancer, ovarian cancer, pancreatic cancer, and melanoma (Jacquelot, Duong, Belz, & Zitvogel, 2018; Kaye et al. , 2012; Linehan et al. , 2018; Shepard & Dreicer, 2010). However, their potential remains largely untapped. Sequencing methods have revealed a list of genes driving tumor initiation and demonstrated GPCR overexpression in various cancer types (Lappano & Maggiolini, 2011). Recent studies have also raised the question whether mutations in GPCRs are driving cancer progression or if they represent passenger mutations with little impact (Kan et al. , 2010; Kandoth et al. , 2013; Lawrence et al. , 2013). In this review, we discuss the involvement of GPCR signaling in cancer development and immune response, and the mutational landscape of G proteins and GPCRs. Subsequently, we provide evidence of GPCR mutations as cancer driver or passenger genes. Lastly, we summarize the challenges and opportunities of targeting GPCRs in cancer therapy.Table 1 Currently FDA approved anti-cancer drugs targeting GPCRs.