Декодирование GPCR, сигнализирующее перепрограммирование рака: молекулярные механизмы и терапевтические последствия.

Introduction

In the human genome, more than 2% of genes encode G protein-coupled receptors (GPCRs), which are considered the largest family of protein receptors, including over 800 members (Fredriksson and Schiöth 2005 ). They perform a crucial function in the body by regulating signal transduction by acting as gatekeepers for agonists and antagonists. They regulate many drugs and hydrophilic hormones that cannot penetrate the cell membrane easily, and conduct cascades of signaling to trigger responses intracellularly (Insel et al. 2007 ). Furthermore, a wide range of extracellular stimuli, such as environmental cues, proteins, small peptides, ions, and neurotransmitters, are recognized by these receptors. These signals regulate metabolism, growth, and several physiological processes (Insel et al. 2007 ). However, GPCR dysfunction contributes to many common human diseases.

GPCRs are characterized by seven transmembrane α-helices (7TM) embedded in the plasma membrane. The N-terminus is located extracellularly, followed by the seven transmembranes (TM1 to TM7), which are connected with three extracellular loops (ECL-1 to ECL-3). Intracellularly, the transmembrane domains are linked via three intracellular loops (ICL-1 to ICL-3) and end with the carboxyl terminus (C-terminus) helix 8 (H8) (Katritch et al. 2012 ; Chaudhary and Kim 2021 ).

Based on structural and sequence homology, GPCRs are classified into five families: rhodopsin (Family A, 672 members), secretin (Family B1, 15 members), adhesion (Family B2, 33 members), glutamate (Family C, 22 members), and frizzled/taste2 (Family F, 36 members) (Katritch et al. 2012 ; Hilger 2021 ). In the previous review by Wu et al., they focused on the GPCR landscape of alterations and aberrations by integrating genomic and transcriptomic datasets, such as expression profiling, mutation analysis, and CNV of GPCR genes, to demonstrate the impact of these receptor mutations in modulating the tumor microenvironment and progression. They also discussed oncocrine signaling networks, including paracrine, autocrine, and microenvironmental interactions, that shape tumor progression and immune evasion, with a focus on tumor precision immunotherapies (Wu et al. 2019 ).

Meanwhile, this study focuses on GPCR intracellular signaling pathways, in which dysregulation in downstream signaling cascades leads to the reprogramming of cancer cell behavior. It also expands the analysis by integrating multiple genomic landscapes, including epigenetic modulation, post-transcriptional control, and post-translational modifications, with a focus on targeting these receptors through combinations of drug inhibitors to overcome tumor resistance. In addition, as receptor expression heterogeneity across multiple tumors presents a hurdle for early diagnosis and drug efficacy, we discuss cancer theranostics as a highly promising approach in precision medicine.

Methods and analysis

Search engines and date range

We structured a comprehensive search strategy of the available literature in academic databases including PubMed, EMBASE, Web of Science, and Scopus to identify the role of GPCRs in driving cancer progression. In addition, a supplementary search was conducted within the Cochrane Database of Systematic Reviews (CDSR) to ensure comprehensive coverage of indexed reviews. This review extracted biomedical articles published in English language between January 2010 and 31 December 2025 and included the MeSH terms or following keywords: neoplasms, epigenomics, genetic, neoplasms, autocrine communication, paracrine communication, immune system receptors, G-protein-coupled, smoothened receptor, CXCR4, CCR5, chemokine CCL5, chemokine CXCL12, mitogen-activated protein kinases, extracellular signal-regulated MAP kinases, inositol 1,4,5-trisphosphate, type C phospholipases, guanine nucleotide exchange factors, rapguanine nucleotide exchange factor 3, phosphatidylinositol 3-kinases, proto-oncogene proteins c-akt, TOR serine-threonine kinases and antineoplastic agents.

Search strategy

All databases were searched using the combination with the MeSH terms “Neoplasms” or “cancer” with one of the above MeSh terms or words in the titles of publications to provide the initial database for the review. For example the search strategy utilized the following parameters: ("Smoothened Receptor"[MeSH Terms] OR "SMO"[Title/Abstract] OR "Smoothened"[Title/Abstract]) AND ("Neoplasms"[MeSH Terms] OR "Cancer"[Title/Abstract] OR "Oncology"[Title/Abstract]) AND ("2010/01/01"[Date—Publication]: "2025/12/31"[Date—Publication]) AND English[Language].

Initial search was carried out in late January 2025, twice in April, and July 2025 and once for a final update in December 2025 by two researchers. To supplement the electronic database results, a manual search for additional references was conducted.

Selection criteria

A predefined inclusion and exclusion criteria have been set before screening. Eligibility criteria for inclusion were all review papers that published in English language, and reviewed cancer immunotherapy. All other papers were excluded.

Results

A total of 3,217 unique review articles were identified through electronic database searches, supplemented by 16 additional records identified through manual searching. Following the removal of duplicates, commentaries, and brief communications, 1,912 records remained for initial title and abstract screening. Of these, 202 articles met all eligibility criteria and were included in the final review. The selection workflow is illustrated in Fig. 1 . Fig. 1 The studies selection flowchart

Background

There are two major GPCRs signaling pathways, the first is G-protein-dependent manner (canonical). In this pathway, receptor couples to three subunit proteins (Gα, Gβ, and Gγ) known as heterotrimeric G-proteins. The Gβ and Gγ subunits are tightly bound and function together as a Gβγ dimer. The Gα is classified into Gαs, Gαi/o, Gαq/11, and Gα12/13, in which there are four families, each mediating distinct downstream signaling pathways (Chaudhary and Kim 2021 ). In the inactive state, Gα is bound to guanine nucleotide GDP (Insel et al. 2007) (Fig. 2 ). Fig. 2 GPCRs pathway signaling. (i) a G-protein-dependent manner, where the ligand binds to the extracellular domain of the receptor, converting Gα-GDP (inactive state) to Gα-GTP (active state), which causes dissociation of the heterotrimer into Gα and the Gβγ dimer. Each Gα isoform and the Gβγ dimer regulates distinct signaling pathways by activating specific second messengers; (ii) regulatory and scaffolding roles of G-protein-independent manner (arrestin- dependent), upon receptor activation, G protein–coupled receptor kinases (GRKs) are recruited, which subsequently resulting in C-terminal phosphorylation, leading to two distinct functions of arrestin-pathway, blocking the engagement of G-protein to halt signaling activation of the activated receptors and initiating the machinery of the clathrin-dependent endocytic (initiates receptor endocytosis), in which receptors are degraded via lysosomes or recycled to cell surface. Arrestins also function as scaffolding proteins for downstream signaling pathways

While the second signaling pathway is the G-protein-independent manner (non-canonical) through β-arrestins, in which the ligands bind to the extracellular part of the receptors, GPCR kinases (GRKs) phosphorylate the intracellular domains of the activated receptor, promoting β-arrestin recruitment and binding to phosphorylated receptor clusters. In many GPCR systems, arrestin binding primarily functions to inhibit further G-protein coupling, thereby terminating G-protein–mediated signaling (desensitization). In other cell contexts, such as hormone-responsive GPCRs, arrestin recruitment also facilitates clathrin-mediated endocytosis and receptor internalization, leading to receptor downregulation or recycling. In addition, arrestins can act as scaffolding proteins that initiate distinct downstream signaling cascades, such as the MAPK and ERK pathways, independently of G proteins, as shown in Fig. 2 (Katritch et al. 2012 ; Chen and Tesmer 2022 ).

Signal transduction via the GPCR starts when an agonist ligand, such as neurotransmitters, photons, ions, and hormones, binds to receptors at the outer surface of the cell membrane. This binding results in receptor activation, altering the intracellular loops and transmembrane helices due to conformational change induction via ligand binding. Consequently, on the inner plasma membrane surface, the activated receptor couples to a heterotrimeric G protein and stimulates secondary messenger systems via modulating downstream protein effectors by inducing the exchange of GDP for GTP on the Gα subunit. The Gβγ dimer dissociates from the Gα subunit following Gα activation (O’Hayre et al. 2013 ; Rosenbaum et al. 2009 ; Martínez-Morales et al. 2022 ).

The dissociated Gβγ and Gα-GTP activate their respective cognate effectors on the condition that Gα is maintained in the GTP-bound state and the Gβγ effector interface is accessible for direct interaction with its effectors to regulate cell growth, cell survival, and gene transcription. Signal termination occurs when Gα hydrolyzes GTP to GDP and reassociates with Gβγ to reform the inactive heterotrimer. This process is accelerated by regulators of G protein signaling (RGS) proteins that turn off the activated Gα-GTP by facilitating the GTPase that hydrolyzes GTP (guanosine triphosphate) to GDP (guanosine diphosphate) (O’Hayre et al. 2013 ).

CAMP-PKA/EPAC pathways

Intracellular signaling cascades are initiated by extracellular first messengers, including ions, hormones, and growth factors, which subsequently activate the second intracellular signaling messengers, like cyclic adenosine monophosphate (cAMP), calcium ions, or cGMP. Tight regulation of these second messengers is essential. Their dysregulation contributes to tumor initiation and progression. cAMP is a major second messenger that regulates cell differentiation and proliferation. Aberrant cAMP signaling promotes carcinogenesis and alters the tumor microenvironment (TME) in a cell type– and context-dependent manner (Zhang et al. 2020 ).

cAMP is generated through GPCR-dependent mechanisms involving heterotrimeric G proteins and through GPCR-independent mechanisms mediated by soluble adenylyl cyclase (sAC). When β2 receptor agonists, GLP-1, or PGE2 ligands bind to their respective GPCRs, the Gαs subunit undergoes GDP–GTP exchange and functionally dissociates from the Gβγ dimer to activate the adenylyl cyclases (ACs) that catalyze the conversion of ATP to form cAMP. In contrast, cAMP can also be generated independently of GPCRs through soluble adenylyl cyclase (sAC), which is activated by intracellular calcium ions (Ca 2 ⁺) and bicarbonate (HCO₃⁻). sAC is localized to discrete intracellular compartments, including the cytoplasm, mitochondria, and nucleus, where it generates spatially restricted cAMP microdomains. These microdomains enable compartment-specific regulation that is physically and functionally insulated from plasma membrane–associated transmembrane adenylyl cyclases (tmACs). Such compartmentalization provides precise spatial control of cAMP signaling, which is particularly important in cancer cells, as it allows localized signaling that regulates metabolic rewiring and apoptosis while avoiding cytotoxic effects associated with global cAMP elevation (Zippin et al. 2004 ; Ramos-Espiritu et al. 2016 ; Drozdz et al. 2022 ). Ion channels, exchange protein directly activated by cAMP (EPAC), and protein kinase A (PKA) are the downstream effectors activated by cAMP (Fig. 3 ). Fig. 3 cAMP signaling pathways and downstream effectors. cAMP is generated through two mechanistically distinct pathways: (i) G-protein-dependent manner, the dissociation of the Gαs from the dimer Gβγ subunits, leading to the activation of the adenylyl cyclases (ACs), which form the cAMP by catalyzing the conversion of ATP into cAMP (tmAC-derived cAMP; global signaling at the plasma membrane); and (ii) GPCR-independent manner, bicarbonate (HCO 3 - ) and calcium ions activate the soluble adenylyl cyclase (sAC) to synthesize cAMP(sAC-derived cAMP; localized microdomain signaling within intracellular compartments including the cytoplasm, nucleus, and mitochondria). These sAC-generated cAMP microdomains enable compartmentalized signaling that is functionally independent from plasma membrane–associated tmACs. However, cAMP is degraded to adenosine 5-monophosphate (5’AMP) via phosphodiesterases (PDEs). The cAMP regulates three different downstream protein effectors: the protein ion channel, associating in the regulation of the heart rate, olfactory transduction, and calcium signaling pathways; holoenzyme PKA (two C subunits, two R subunits), C subunits phosphorylate transcription factor (CREB) responsible in regulating the CRE genes with the association of CBP and CRTCs coactivators, and, the phosphorylation of specific targets by PKA particular, due to the A kinase anchor proteins (AKAPs), anchoring the PKA in localized sites; EPAC/Rap pathway activate different signaling, implicating in many biological and pathophysiological processes via Rap1/2 activation, through releasing the Rap1 and Rap2 (Ras family proteins) the GDP and binding to GTP to activate the Rap1/2. Furthermore, sAC-derived cAMP microdomains in the nucleus and mitochondria contribute to the regulation of metabolic rewiring and apoptosis

Moreover, cAMP modulates ion channels, including hyperpolarization-activated cyclic nucleotide-gated (HCN) channels and cyclic nucleotide-gated (CNG) channels. Binding of cAMP promotes channel opening and regulates membrane excitability through potassium, sodium, and calcium fluxes (Ahmed et al. 2022 ). The activation of EPAC stimulates various signaling pathways, such as Raf/Ras/MAPK, PI3K/Akt/mTOR, and PLCε, which are involved in multicellular processes like adhesion, migration, and cell growth.

Depending on the stimulus, EPAC can promote ferroptosis, parthanatos, or inhibit apoptosis (Zhang et al. 2020 , 2024 ). Upon activation, PKA phosphorylates the transcription factor cAMP response element-binding protein (CREB). CREB regulates oncogenes such as cyclin D1 and c-Jun. Moreover, the signaling of cAMP–PKA–CREB can be both a tumor promoter or tumor suppressor, depending on the cancer type. On the other hand, cAMP is degraded via phosphodiesterases (PDEs). Approximately 22 phosphodiesterases (PDEs), in coordination with adenylyl cyclase inhibitors (Gαi) and activators (Gαs), play a crucial role in maintaining intracellular cAMP levels (Zhang et al. 2020 ).

Phosphatidylinositol (IP3/PLC) signaling pathway

Phosphatidylinositol(4,5)-bisphosphate (PI(4,5)P₂) (PIP2) is a phospholipid that results from phosphatidylinositol (PI) phosphorylation in the endoplasmic reticulum (ER) and is located at the cell membrane, having a wide range of functions. One of its most crucial functions is signal transduction via GPCR receptors. When a ligand, such as a hormone, binds to the GPCR receptor, Gαq dissociates from the Gβγ subunit. Subsequently, Gαq triggers the activation of phospholipase Cβ (PLCβ). This enzyme then hydrolyzes PIP2 to yield two-second messengers: inositol 1,4,5-trisphosphate (IP₃) and diacylglycerol (DAG)(Katan and Cockcroft 2020 ). DAG is a signaling lipid involved in the activation of protein kinase C (PKC), PA, and ion channels. The second messenger IP₃ is soluble and diffuses intracellularly, where it interacts with the endoplasmic reticulum (ER) membrane receptors (IP3Rs) and triggers the release of calcium ions (Ca 2 ⁺), resulting in an elevation of cytosolic Ca 2 ⁺ levels (Fig. 4 A) (Rubio et al. 2018 ; Kanemaru and Nakamura 2023 ). Fig. 4 Inositide-dependent signaling pathways. A Phospholipase Cβ (PLCβ) is activated by the Gαq, hydrolyzing the PI(4,5)P2 IP3 and DAG second messengers; IP3diffuses and interacts with the endoplasmic reticulum (ER) membrane receptors, elevating the cytosolic calcium level; along the cell membrane, DAG diffuses and targets many kinases, calcium-sensitive enzymes, and ion channels, enabling further biological processes. B After GPCR receptor activation, G-proteins activate PI3K to convert PIP2 to PIP3, which recruits PDK1 and one of the mTOR complexes (mTOR complexes (mTOR complex 2 (mTORC2)). Thereby, activating Akt to phosphorylate essential cytoplasmic proteins and two tumor suppressor proteins, PRAS40 and TSC2, hence activating the other complex of mTOR (mTOR complex 1 (mTORC1)), which is responsible for regulating cell metabolism and growth proteins

PLC reduces the presence of PIP2 due to the hydrolysis process, which affects the lipid integrity of the membrane. Hence, ion channels, actin dynamics, and endocytosis regulate this process with the aid of the compartmentalization of PIP2 into membrane nanodomains, which facilitates the simultaneous regulation of these diverse cellular activities(Katan and Cockcroft 2020 ). PKC has a vital function in various cell types, and it is known to belong to phospholipid dependent serine/threonine kinase family, which has three subfamilies: classical PKC isozymes (cPKCs), nonclassical PKC isozymes (nPKCs), and atypical PKC isozymes (aPKCs). Those isozymes are involved in diverse effects in cancer cells, such as angiogenesis, apoptosis, migration, invasion, tumor cell survival, proliferation, and drug resistance(Kang 2004 ).

PI3K/Akt/mTOR pathway

Here, another important pathway of inositide-dependent signaling is essential for cellular differentiation and proliferation. On the contrary, its dysregulation frequently leads to tumor progression. The PI3K/Akt/mTOR has two vital components controlling its regulation: the PI3K, which phosphorylates the phosphatidylinositol(4,5)-bisphosphate (PIP2), producing phosphatidylinositol(3,4,5)-trisphosphate (PIP3) to activate the pathway, while PTEN (tumor suppressor) deactivates the Akt activation through the conversion of PIP3 to PIP2 (Follo et al. 2015 ). Upon GPCR receptor activation, G-proteins (Gα: G12/13, Gi/o, Gq, Gs, and Gβγ) can all activate PI3K to produce PIP3, which subsequently recruits mTORC2 and PDK1 to activates Akt (Ser/Thr kinase) (Sun et al. 2023 ). The activation of Akt phosphorylates PRAS40 or TSC2, leading to mTORC1 activation, which therefore regulates downstream proteins associated with cell metabolism and growth (Fig. 4 B) (Follo et al. 2015 ; Glaviano et al. 2023 ; Desale et al. 2021 ; Guo et al. 2020 ). Furthermore, the AKT activation itself phosphorylates and regulates various functional proteins like GSK-3, p27, p21, CHK1, MDM2, FOXO, IKKα, and BAD (Glaviano et al. 2023 ).

ERK/MAPK pathway

Mitogen activated protein kinase (MAPK), in humans, is one of the crucial protein families that is activated in response to various stresses, including cytokines, mitogens, and heat. Activation of MAPKs occurs in three cascade steps and consist of 24 MAPK kinase kinases (MAP3Ks), the initiator of the signaling pathway through phosphorylation and activation of 7 MAPK kinases (MAP2Ks); MAP2K, passing the signal downstream, phosphorylating and activating 14 MAPKs; MAPK, which regulates and activates proteins that control a variety of cellular processes, such as proliferation, gene expression, differentiation, cell survival, and cell death. This family consists of four groups, p38 (p38α/δ), JNK (Jun N-terminal kinase) (JNK1-3), ERK (extracellular signal-regulated kinase) (ERK1/2), and BMK (big MAPK or ERK5) (Kim et al. 2022 ; Peterson et al. 2022 ). GPCR receptors trigger multiple intracellular signaling pathways via activation of G proteins after ligand binding. Subsequently, they initiate downstream MAPK group cascades: JNK and p38, associated with stress and apoptotic signals; ERK, linking to cell growth and survival; and ERK5, regulating cellular differentiation, proliferation, and migration. However, the most crucial pathway of the MAPK pathways is the Ras/Raf/MAPK (MEK)/ERK pathway, which regulates tumor cell development and survival (Guo et al. 2020 ; Peterson et al. 2022 ).

GPCRS role in cancer

Although the vital role of regulating multicellular functions like cellular growth, proliferation, differentiation, and even cell apoptosis, GPCR are also linked to numerous diseases and tumorigenesis, in which its abnormality in signaling reprogramming of the receptors, overexpression or losing genomic integrity leads to various pathological effects, including inflammation, genomic instability, apoptosis resistance, metabolic remodeling, and subsequently leading to carcinogenesis, as well as, angiogenesis, cancer cell proliferation, metastasis, and invasion (Dorsam and Gutkind 2007 ; Arang and Gutkind 2020 ).

Mutations and aberrant gene expression

These receptors are associated with the functioning of multiple tissues, and the human genome comprises about 600 GPCRs, in which they are regulated and expressed under the control of multiple genomic landscapes, starting with Copy Number Variation (CNV), pre-transcriptional (epigenetic), post-transcriptional (miRNA regulation) and post-translational levels (protein level) (Hwang et al. 2022 ). The abnormality in one of those levels leads to disturbed cellular functionality and cancer cell development.

Copy Number Variation (CNV)

The structural variation in chromosomes, in which DNA sections are lost (deleted) or amplified (duplicated), is known as Copy Number Variation (CNV) (Freeman et al. 2006 ). The variation of genomic copy numbers is connected to chromosomal rearrangement; however, they are not correlated as much with the expression of mRNA dysregulation associated with GPCRs CNV, which is explained by a study conducted to assess the GPCRs' role in multiple solid tumors using the CNV, mutations, and mRNA expression to correlate between them.

The finding suggests that GPR160 is frequently amplified, while in Kidney cancer (KIRC), PTH1R is deleted; nevertheless, those findings are not clear enough to correlate GPCR mRNA expression dysregulation with CNV (Sriram et al. 2019 ). In contrast, another study shows that CNV in GPCR: MRGPRX1 deletion, MC4R deletion, and neuropeptide SCT (secretin) amplification, which are found in neuroendocrine prostate cancer and pancreatic cancer, are highly dominant and can be considered as valuable markers for treatment and diagnosis (Zhao et al. 2017 ).

Pre-transcriptional level

At the epigenetic level, there are three major patterns of epigenetic modulation, and any modification upon them will lead to disrupting the normal functioning of a cell, leading to tumor development and progression. These modifications are DNA methylation, histone modifications, and chromatin remodeling, in which any dysregulation among them leads to promoting cancer development and metastasis (Gu et al. 2024 ).

The first pattern is DNA methylation (methylation of CpG islands), which is a process that can attack about 60% of human promoters, adding a methyl (CH₃) group at 5' position of the cytosine ring, forming 5-methylcytosine (5mC) by DNA methyltransferases (DNMTs) at sites that have dinucleotide repeats of CG (cytosine preceding guanine) called CpG islands. However, adding a methyl group at those sites blocks transcription factors' binding to promoters, which causes genes to be switched off and silenced (Zhu et al. 2016 ; Bouyahya et al. 2022 ).

Recent studies have shown that many ligands and their GPCRs are highly regulated through the methylation processes, with a correlation to survival. For instance, Neuroendocrine tumors (NETs) have been linked to somatostatin (SST) gene hypomethylation, in which it’s highly expressed, while when this gene promoter is hypermethylated, it causes cancer growth inhibition through reduction of somatostatin’s ability (Byun et al. 2021 ). In aldosterone-producing adenoma (APA), PTGER1, GRM3, TACR1, MC2R and HTR4 GPCRs genes revealed a hypomethylation pattern, in which their gene expression is upregulated in APA (Itcho et al. 2018 ).

Furthermore, in thyroid carcinoma (THCA), uveal Melanoma (UVM), rectum adenocarcinoma (READ), and adrenocortical carcinoma (ACC), about 8 GPCR genes (PIK3R6, OR6F1, OR2L13, OR1C1, NECAB2, GRK5, F2RL3, and DGRK), their expressions are found to be controlled by DNA methylation (Zhang et al. 2022 ). Also, In omics study revealed that the about 252 GPCR genes with 504 regions found to be regulated by DNA methylation in Prostate cancer (PRAD), which have 243 hypermethylated regions, and 261 hypomethylated regions (Li et al. 2022 ).

The second pattern is histone modifications, which occur at the histone core, consisting of eight octamer proteins (H2A, H2B, H3, and H4). Those proteins are positively charged with high alkalinity; hence, they form a core that the negatively charged DNA can attract to and wrap around tightly, forming a state of compaction (inaccessible for transcriptional activity); therefore, genes are silenced in this state. However, many chemical modifications can alter this state, from compaction to decompaction, like acetylation and methylation, which are considered the major modifications that can alter the GPCR gene expression (Sun et al. 2022 ). While the acetylation process mainly involves Histone Acetyltransferases (HATs) enzyme to add an acetyl group to lysine at the N-terminal in H3 histone to alter the positive charge to be neutral, thus DNA becomes loose and accessible for transcription, the Histone Deacetylase (HDAC) removes the acetyl group, which reverses the process and silences the expression (Grazioli et al. 2017 ).

Another dynamic modification is methylation, which is represented in transferring methyl groups from S-adenosylmethionine (SAM) molecules via histone methyltransferases (HMTs) into the arginine and lysine N-terminal tail of H3/H4 histone; in contrast, removing a methyl group is done via histone demethylases. Although the DNA charge doesn’t alter upon adding methyl groups, the number of methyl groups added one to three times on specific histone residues create docking sites that alter the state of the chromatin compaction to be either activate (decompact) or repress (compact) gene transcription (Greer and Shi 2012 ).

For instance, in bone cancer pain (BCP) that linked to GPR160 expression found to be modulated via histone methylation and acetylation, in which the hyperacetylation (histone H3 (H3K27) at lysine 27) and hypomethylation at the promoter of this gene causes SP1 transcription factor to bind to the promoter and increases the gene expression, leading to sensitization of the peripheral neuron and pain onset. In contrast, H3K27 trimethylation leads to gene repression and halts neuron sensitization (Xu et al. 2024 ). In chemoresistant cells of ovarian cancer, the regulator of G-protein signaling 2 (RGS2) is suppressed, which is normally functioning as a GTPase-activating protein that inhibits the GPCRs; thus, the suppression of RGS2 leads to hyperactivation of the GPCRs. This deactivation of RGS2 is due to the methylation and deacetylation occurring at the RGS2 promoter via DNA methyltransferase I (DNMT1) and histone deacetylases (HDACs), respectively (Cacan 2017 ).

In colon cancer, the epigenetic tumor suppressor FFAR2 is a G protein-coupled receptor (GPCR) known as GPR43. It functions in halting cancer progression. When FFAR2 is deficient, this leads to hyperactivation of the cAMP–PKA–CREB signaling pathway. As a result, histone deacetylases (HDACs) are overexpressed, causing hypermethylation of inflammation suppressors and decreasing their expression (Pan et al. 2018 ).

Post-transcriptional (miRNA regulation)

Gene expression at the post-transcriptional level can be regulated via a group of endogenous microRNAs, a noncoding RNA with 22 nucleotides (single strand), which are complementary to mRNAs’ untranslated UTR regions. The binding of miRNA to the targeted mRNA causes degradation of the mRNA, which plays a crucial role in regulating cell differentiation, proliferation, migration, and programmed cell death by controlling protein production. In addition, they are functioning as either oncogenes or tumor suppressors; therefore, any dysregulation of miRNA expression leads to tumor progression (Casamassimi and Ciccodicola 2019 ).

GPCR-related gene expression has been found to be regulated via miRNAs, for instance, in hepatocellular carcinoma (HCC), miR-34a-5p, miR-494-3p, and miR-155-5p have proved to be involved in GPCR-related gene dysregulation (Wang et al. 2024 ). In gastric cancer, COPS8 and CARD10, GPCR signal transduction mediators that activate the NF-κB, which induces the transcription of pro-inflammatory growth factors, cytokines, and other tumor-promoting genes. The miR-146a regulates NF-κB-activating pathways by targeting COPS8 and CARD10; however, miR-146a is found to be a tumor suppressor, as when it is upregulated, it subsequently targets mediators, leading to NF-κB inhibition (Crone et al. 2012 ). Another tumor suppressor microRNA is miR-126, which is found to be downregulated in many tumors. It is targeting the GPCR pro-metastatic CD97 (ADGRE5), a member of the adhesion G protein–coupled receptor (aGPCR; Family B2) subfamily involved in cell–extracellular matrix interactions, that promotes cell migration, invasion, and angiogenesis; thus, miR-126 downregulation leads to CD97 overexpression and subsequently leads to tumor progression (Lu et al. 2014 ; Aust et al. 2022 ). Mechanistically, miR-126 binds to the 3′-UTR of ADGRE5 mRNA, leading to its degradation and translational repression. In addition, there are other microRNAs, including miR-503-5p, miR-320, miR-21-5p, miR-590-5p, and miR-505-3p, that have been reported to regulate ADGRE5 expression, suggesting a broader post-transcriptional regulatory network. Furthermore, the edited miR-379-5p adenosine to inosine (A-to-I) targets the ADGRE5 gene and suppresses its expression, which promotes apoptosis and is associated with patients' survivability (Aust et al. 2022 ).

The activity of Gα subunits in the GPCR signaling networks is also regulated via microRNAs. For instance, RGS17 is one of the regulators of G protein signaling (RGS) members that are normally expressed in the central nervous system and function in turning off the activity of the Gα subunits. It is found to be abnormally upregulated in many cancers, where it promotes proliferation, invasion, and migration. In breast cancer, miR-32 is found to be downregulated, and RGS17 is its target; thus, RGS17 is upregulated, which leads to increased tumor progression. In addition, in some lung cancer cell lines, RGS17 is regulated via miR-182, and the expression of miR-182 is downregulated in these lines, resulting in the overexpression of RGS17 (Hayes and Roman 2016 ).

Post-translational levels

After translation, proteins can undergo covalent changes known as post-translational modifications (PTMs). Those modifications play vital roles in maneuvering protein localization, stability, activity, and interactions. Protein properties are changed via those modifications either by adding a modified group to amino acids or by proteolytic cleavage (Mann and Jensen 2003 ; Seo and Lee 2004 ). The most common modifications that modulate signaling, dimerization, trafficking, and receptor folding of proteins in GPCRs are phosphorylation, glycosylation, palmitoylation, and ubiquitination, which control physiological responses and the temporal and spatial dynamics of receptor signaling. These modifications are localized at many domains, ranging from the N-terminus to the C-terminus of the GPCRs and are accessible to PTM-enzymes.

Nevertheless, any GPCR PTMs Disorders can lead to deficient signaling responses and consequently lead to cancer, immune dysfunction, and other diseases (Zhang et al. 2022 ). For instance, a tumor suppressor, a-arrestin domain containing-protein-3 (ARRDC3), controls GPCR traffic signaling via ubiquitination and degradation of the activated protease-activated receptor-1 (PAR1). In breast cancer (invasive basal-like), the ARRDC3 is suppressed; subsequently, the E3 ubiquitin ligase-mediated ubiquitination process of PAR1 is inhibited; thus, PAR1 remains active and cannot be degraded via lysosomes, which remain internalized and recycled. Subsequently, signal transduction persists, promoting tumor progression and invasion (Arakaki et al. 2018 ).

Pathways

The independent and dependent GPCR pathways can be stimulated by different conformational activities, which change the dynamic activity of receptors and initiate diverse downstream events that modulate cellular growth, proliferation, and cell death. Therefore, abnormal pathways function lead to various tumorigenesis and diseases. The diverse GPCR-regulated signaling pathways implicated in cancer progression, and the major GPCRs involved in different cancer types with their endogenous ligands, downstream signaling pathways, associated receptors, and the resulting pathophysiological effects have been illustrated in Table 1 . These pathways include GPCR-mediated transactivation of receptor tyrosine kinases (RTKs), activation of β-catenin signaling, chemokine-driven signaling cascades and various signaling pathways, all of which are well-established contributors to cancer progression, invasion, and metastasis. Table 1 GPCR signaling pathways in cancer Cancer Receptor Ligand Pathway Rationale Pathophysiological effects Ref Liver cancer EP4 PGE2 EP4R/GS/AC/cAMP/PKA/CREB signaling pathway Hyperactivation of the EP4 receptor upregulates the expression of c-Myc protein through activating the cAMP/CREB/PKA pathways Growth, invasion (Xia et al. 2014 ) Colorectal cancer EP4 PGE2 COX-2 pathway Overexpression of COX-2, increasing bcl-2 expression, and decreasing the TGF receptor expression Tumor progression,decreasing Apoptosis,metastasis (Greenhough et al. 2009 ; Brown et al. 2005 ) LPA 1 LPA LPA/β-catenin signaling pathway LPA stimulated nuclear accumulation of β-catenin, which controls lymphoidenhancing factor/T T cell–factor family (Lef/Tcf) gene expression Progression, Proliferation (Lin et al. 2021 ; Malbon 2005 ) ETAR, ETBR ET-1 β-catenin pathway An increase in β-catenin signaling leads to overexpression of the ET-1 gene Progression, Survival (Kim et al. 2005 ; Growcott 2009 ) PAR1 F2 PAR/MAPK/Rho signaling pathway Overexpression of PAR1, thrombin activates platelets and endothelial cells, and cleaves fibrinogen to generate fibrin, serving for angiogenesis Growth, invasion, metastasis (Arora et al. 2009 ) Frizzled Wnts Wnt/β-Catenin Signaling (Canonical) Inactivation of APC leads to the destabilization of β-catenin Progression, Proliferation (Lai et al. 2009 ; Liu et al. 2022 ) Breast cancer PAR1 F2 Transactivation of ErbB1 and ErbB2 Hyperactivation of ErbB signaling Metastasis, invasive breast carcinoma (Arora et al. 2008 ) EP2, EP4 PGE2 COX-2 pathway COX2 overexpression, synthesizing the PGE2, thus activating the EP2 and EP4, initiating signaling pathways: cAMP/PKA/PI3K Growth, metastasis, angiogenesis (Dorsam and Gutkind 2007 ; J. R, D. H, A. F. 2011 ) CXCR4 CXCL12 CXCL12/CXCR4 signaling pathway Tyrosine kinase receptors, transactivation as FGFR, IGF-1R, and ErbB1 Metastasis, invasive breast cancer (Cojoc et al. 2013 ) GPER1 4-OHT GPER1 signaling GPER1 signaling activates CREB. These factors, in turn, activate the expression of the second tier of transcription factors like FOS, ATF3, c-Jun, EGR1, leading to the activation of the CTGF gene Proliferation, metastasis (Pandey et al. 2009 ) Ovarian cancer LPAR1, LPAR2, LPAR3 LPA Gi-Ras-MEKK1 signaling pathway G12/13-RhoA-ROCK signaling pathway Hyperactivation of the pathways, leading to LPA-induced FAK autophosphorylation and membrane redistribution Metastasis (Bian et al. 2006 ) CXCR2 CXCL1 TP53 pathway MAPK signaling pathway Overexpression of CXCL1 activates ErbB1, leading to MAPK pathway activation, while inducing fibroblast senescence by the TP53 pathway Progression, proliferation (Huang et al. 2022 ) Prostate cancer PAR1 F2 PAR/MAPK/Rho signaling pathway Hyperactivation in PAR1, thrombin activates platelets and endothelial cells, and cleaves fibrinogen to generate fibrin, serving for angiogenesis Growth, invasion, metastasis (Chaudhary and Kim 2021 ; Arora et al. 2009 ) ETAR ET-1 β-arr1/β-arr2 & c-Src pathways Overexpression of ET-1R/b-arr1 signaling pathways β-arr2–Src complex, increasing β2 adrenergic receptor stimulation, thus activating ERK1/2 pathway Growth, survival, metastasis (Bagnato and Rosanò 2018 ; Strungs and Luttrell 2014 ) AT1 Ang-II MAPK/STAT3 signaling pathway Hyperactivation of AT1 receptor expression and Ang-II production, inducing MAPK and STAT3 signaling Growth, invasion (Uemura et al. 2008 ) EP4 PGE2 cAMP-PKA/PI3K-Akt signaling pathway Increasing in PGE2 and hyperactivation of EP4 receptor, upregulating the expression of the MMP-2, MMP-9, RANKL and RUNX2 Proliferation, invasion (Xu et al. 2018 ) LPAR1, LPAR2, LPAR3 LPA LPAR signaling High level of LPA activates ERK/mTOR pathways (suppresses autophagy) and activates Akt/Rho; upregulation in LPAR1, implicated in the induction of reactive oxygen species (ROS) Proliferation, survival, migration (Balijepalli et al. 2021 ) B2R BK Bradykinin signaling pathway Increasing in BK/B2R signaling, upregulating VEGF expression, and activating Akt/mTOR/NF-kB/AP-1 pathway. Also, upregulating MMP-9 and activating B2 receptor, PKCd, c-Src, and NF-kB pathways Angiogenesis, migration (Yu et al. 2013 ; Rex et al. 2022 ) GRPR GRP GRPR/cAMP signaling pathway Overexpression of GRPR increases the cAMP signaling and stimulates DNA synthesis Growth, invasion, migration (Rurarz et al. 2023 ) Melanoma MC1R α-MSH cAMP-PKA signaling pathway UV exposure stimulates keratinocytes to release α-MSH, leading to activation of cAMP/PKA, which phosphorylates CREB, activating the MITF promoter and upregulating melanogenesis enzyme genes Growth, Proliferation, invasion (Raymond et al. 2022 ) CXCR1, CXCR2 CXCL8 PI3K/Akt/MAPK signaling pathways Increasing the secretion of IL-8 by the UV radiation and overexpressing of CXCR1/CXCR2, leading to activating PI3K/Akt/MAPKsignaling pathways Growth, metastasis, angiogenesis, invasion (Adams et al. 2021 ) ETBR ET1, ET2, ET3 Endothelin signaling The activation of ETBR induces the HIF-1α expression, leading to the up-regulation of vascular endothelial growth factor and resulting in the Akt/MAPK pathways, which up-regulate a MCAM Invasion, metastasis (Urtatiz and Raamsdonk 2016 ) Pancreatic cancer GRPR GRP PLC-β/PKC/MAPK signaling pathways GPCR-associated protein mutations and reduction of GTPase activity lead to constitutive signaling activation of PLC-β/PKC/MAPK pathways Growth, Progression (Parascandolo and Castellone 2018 ; Matters and Harms 2018 ) CCK-B CCK, Gastrin Gastrin-CCK receptor pathway Hyperactivation of the CCK-B receptor leads to ERK1/2 pathway activation Growth, proliferation (Smith et al. 2016 ) Lung cancer GRPR GRP GRP/GRPR/ErbB1 signaling pathway Upregulation of GRP/GRPR increases the phosphorylation of ErbB1, subsequently activating the RAS/RAF/MAPK downstream pathway Growth, metastatic (Mattei et al. 2014 ) CCK-A, CCK-B CCK, Gastrin Gastrin-CCK receptor pathway In small cell lung cancer: Hyperactivation of CCK-B receptor, leading to activation of PLCβ/ErbB1 signaling, subsequently activating PKC, PI3K/Ras pathways Growth, survival (Smith et al. 2016 ) CXCR4 CXCL12 PI3K/MAPK signaling pathways Hyperactivation of CXCR4 induces focal adhesion components (FAK and Pyk2) phosphorylation, which activates PI3K/MAPK signaling pathways Growth, metastasis (Otsuka and Bebb 2008 ) EP2 PGE2 MAPK/ERK signaling pathway Overexpression of COX-2 activates PGE2-mediated ErbB1independent, activating the MAPK/ERK pathway Growth, proliferation,metastasis, invasion, angiogenesis (Krysan et al. 2005 )

The tumor microenvironment and GPCR–cAMP signaling

The tumor microenvironment (TME) is considered to be a highly dynamic heterogeneous ecosystem, composed of malignant cells, stromal cells, immune infiltrates, neural elements, along with unique biochemical conditions that all together regulate tumor growth, invasion, immune evasion, and metastasis. There are multiple hallmark TME features, such as hypoxia, increased lactate production, extracellular acidosis, and the accumulation of extracellular nucleotides and neurotransmitters that can be predominantly sensed via G protein–coupled receptors (GPCRs), placing GPCR-mediated cyclic adenosine monophosphate (cAMP) signaling as the central regulator of TME remodeling (Zhang et al. 2024 ; Arneth 2019 ; Justus et al. 2013 ).

Hypoxia is one of the characteristics of solid tumors and is considered a potent driver of cAMP signaling. For instance, Hypoxia-inducible factor 1α (HIF-1α) induces the expression of adenylate cyclase isoforms VI and VII, leading to elevated intracellular cAMP levels and enhanced protein kinase A (PKA) activity. Subsequently, it promotes tumor cell migration and invasion (Simko et al. 2017 ). Meanwhile, the tumor cells produce a metabolic byproduct, lactate, via aerobic glycolysis that functions as a signaling molecule within the TME. Lactate activates the GPCR GPR81, which subsequently modulates cAMP–PKA signaling to stimulate production of extracellular vesicles, increase malignancy, and resistance to chemotherapy, as observed in CRC preclinical therapy via regulating repair system mismatches, highlighting the role of metabolic GPCR signaling in tumor adaptation and progression (Qu et al. 2021 ; Luo et al. 2022 ).

As a consequence of glycolytic metabolism, persistent hypoxia, and inadequate blood perfusion in the tumor cells, the TME acquired acidic pH. Acidic pH exerts pleiotropic effects on tumor progression by regulating proliferation, migration, invasion, and metastatic potential of tumor cells, and also affects therapeutic response. In addition, TME acidosis simultaneously reshapes the functions of immune cells, vascular cells, and other stromal components (Justus et al. 2013 ). A family of G-protein receptors, such as GPR4, GPR65 (TDAG8), GPR68 (OGR1), and GPR132 (G2A), can sense the extracellular acidosis within the TME. These receptors are activated by protonation of specific histidine and acidic residues under low-pH conditions and predominantly signal through Gαs proteins, leading to adenylate cyclase activation and intracellular cAMP accumulation. The elevation of cAMP signaling in acidic environments enhances tumor cell migration and invasion, promotes angiogenesis through increased secretion of pro-angiogenic cytokines such as IL-6, IL-8, and VEGFA, and therefore, facilitates immune evasion by upregulating immune checkpoint molecules, including PD-L1 (Justus et al. 2013 ; Harmon et al. 2019 ; Stolwijk et al. 2023 ).

In addition to metabolic and hypoxic signaling, which can further shape cAMP dynamics within the TME. The rise of extracellular ATP due to cellular stress and death is converted via CD39 and CD73 into adenosine, which subsequently activates A2a and A2b adenosine receptors, both of which are Gαs-coupled GPCRs that robustly elevate cAMP levels and trigger downstream signaling through PKA and EPAC (Vijayan et al. 2017 ; Guieu et al. 2022 ). As a result, it can directly promote tumor cell adhesion, proliferation, survival, and migration.

Furthermore, in immune cells, the activation of A2aR/A2bR on cytotoxic T cells, NK cells, and other immune effector cells leads to elevated cAMP levels, which suppress T cell receptor signaling, cytokine production, proliferation, and cytotoxic activity. Subsequently, contributes to functional impairment and exhaustion of T cells, weakening antitumor immune surveillance and enabling immune escape.

The adenosinergic pathway has become an attractive therapeutic target due to its role in promoting tumor cell aggressiveness and suppressing antitumor immunity. Novel therapeutic strategies include monoclonal antibodies and small-molecule inhibitors targeting key components of this pathway, such as CD39, CD73, A2aR, and A2bR. Many of these agents have been progressed into clinical trials for patients with advanced cancers, but it is more effective when combined with standard treatments (chemotherapy, radiotherapy) or immunotherapies (immune checkpoint inhibitors), as they may help overcome resistance driven by the immunosuppressive tumor microenvironment(Vijayan et al. 2017 ).

In cancer-associated fibroblasts (CAFs), GPCR–cAMP signaling plays an important role in coordinating crosstalk between tumor cells and stromal components. The acidic microenvironment promotes the upregulation and activation of GPR68 in CAFs, leading to cAMP synthesis elevation and PKA activation, resulting in elevated IL-6 secretion. This reciprocal signaling loop stimulates tumor immune evasion, cell proliferation, and sustains chronic inflammation. Moreover, cAMP signaling influences fibroblast differentiation, adipogenesis, and metabolic reprogramming, further reinforcing a tumor-supportive stroma (Orange et al. 2023 ; Wiley et al. 2018 ).

The role of GPCRS in cancer therapy

G protein–coupled receptors (GPCRs) represent one of the largest families of druggable targets in human biology and play important roles in cancer signaling, tumor-microenvironment interactions, and immune modulation (Usman et al. 2020 ). Although they have demonstrated success in other areas of therapy, there are limited number of GPCR-targeting anti-cancer strategies validated at the clinical level and approved by the FDA (Figs. 5 A and 4 B). For instance, the Smoothened (SMO) inhibitors that target the Hedgehog signaling were the first FDA-approved GPCR-directed therapies in cancer, in which vismodegib (2012) and sonidegib (2015), as an oncogenic GPCR target, proved their effectiveness against the locally advanced or metastatic basal cell carcinoma (BCC) (Jain et al. 2017 ; Meiss et al. 2018 ). In Table 2 , we have summarized the drugs and antibodies used, along with their GPCR targets and their biomarker applications in various cancer types. Fig. 5 Clinical development landscape and therapeutic modalities of GPCR-targeting anticancer agents. A Bar plot illustrating the distribution of GPCR-targeting therapeutic agents across distinct regulatory and clinical development stages. The Y-axis lists clinical phases and regulatory statuses, ranging from preclinical investigations to FDA-approved therapies and discontinued agents. The X-axis quantifies the number of agents in each phase, revealing that the majority of agents are currently undergoing clinical trials, with a smaller subset approved by regulatory authorities. B Stacked bar plot depicting the distribution of various therapeutic modalities—including antibodies, peptides, small molecules, and theranostics across the same clinical stages. The relative size and color-coded segments indicate the diversity and proportion of drug types present within each stage, highlighting the predominance of small molecules and peptides in active clinical trials and the broader modality representation among approved agents. Together, these panels comprehensively characterize the development pipeline and molecular diversity of GPCR-targeted anticancer therapeutics Table 2 GPCR-Targeted drugs, antibodies, and biomarkers in cancer GPCR Target Ligand/Axis Drug/Antibody Cancer Type(s) Therapeutic Modality Regulatory/Clinical Status Ref AT1R Angiotensin II Telmisartan Non-Small Cell Lung Cancer Small molecules Clinical trials (Patny et al. 2006 ) Losartan, Candesartan Pancreatic Cancer Small molecules Repurposed/observational (Butcher et al. 2025 ) B2R Bradykinin Icatibant Anti-metastatic Peptide Clinical trials (Cai et al. 2024 ) PHA-022121 Metastasis prevention Small molecules Investigational (Lesage et al. 2020 ) Deucrictibant Breast cancer (metastatic) Small molecules Preclinical (Shen and Zhang 2023 ) Glioblastoma Small molecules Preclinical (Shen et al. 2023 ) FR-173657 Anti-invasive Small molecules Preclinical (Shen and Zhang 2023 ; Dubuc et al. 2018 ) CCK2R Gastrin Netazepide Gastric NETs Small molecules Preclinical (Moore et al. 2013 ) CCR2 CCL2 Plozalizumab Advanced melanoma Antibody Clinical trials (Sullivan et al. 2025 ) CCX872 Pancreatic cancer Small molecules Clinical/Preclinical (Linehan et al. 2018 ) CCR4 CCL17/22 Mogamulizumab Sézary syndrome Antibody FDA-approved (Subramaniam et al. 2012 ; Choi et al. 2025 ) Mycosis fungoides Antibody FDA-approved (Subramaniam et al. 2012 ; Choi et al. 2025 ) ATLL IgG1 FDA-approved (Subramaniam et al. 2012 ; Choi et al. 2025 ) CTCL IgG1 FDA-approved (Subramaniam et al. 2012 ; Choi et al. 2025 ) CCR5 CCL5 Leronlimab Metastatic colorectal cancer IgG1 Clinical trials (Jiao et al. 2021 ) Leronlimab Breast cancer IgG1 Clinical trials (Jiao et al. 2021 ) Vicriviroc Colorectal cancer Small molecules Clinical trials (Bessudo et al. 2024 ) Maraviroc Metastatic colorectal cancer Small molecules Repurposed (Pervaiz et al. 2019 ; Casagrande et al. 2018 ; Zhuang et al. 2021 ) Maraviroc Metastatic breast cancer Small molecules Repurposed (Pervaiz et al. 2019 ; Casagrande et al. 2018 ; Zhuang et al. 2021 ) CXCR1/2 CXCL8 (IL-8) SX-682 Multiple solid tumors Small molecules Clinical trials (Patel et al. 2024 ; Johnson et al. 2022 ; Ashraf et al. 2025 ) Reparixin Breast cancer Small molecules Clinical trials (Goldstein et al. 2021 ) Ladarixin Lung cancer Small molecules Clinical trials (Korbecki et al. 2025 ) Navarixin Multiple cancers Small molecules Clinical trials (Armstrong et al. 2024 ) CXCR4 CXCL12 Plerixafor NHL, MM Small molecules FDA-approved (Sison et al. 2014 ) Plerixafor AML/solid tumors Small molecules Clinical trials (Morland et al. 2020 ) CXCR4 CXCR4 axis Balixafortide Metastatic breast cancer Peptide Clinical trials (Ciavattone et al. 2025 ) Ulocuplumab Multiple myeloma Antibody Clinical trials (Ghobrial et al. 2020 ) Motixafortide Multiple myeloma Peptide FDA-approved (Crees et al. 2023b ) CXCR4-RLT AML, MM, lymphoma Theranostic Investigational (Buck et al. 2023 Buck et al. 2022 ) DRD2 Dopamine ONC201 Lung cancer Small molecules Clinical trials (Liguori et al. 2022 ) EP4/EP2 PGE₂ TPST-1495 Endometrial, colorectal Small molecules Clinical trials (Francica et al. 2023 ) EP4 Vorbipiprant Multiple solid tumors Small molecules Clinical trials (Pietrantonio et al. 2024 ) SMO Hedgehog Vismodegib BCC Small molecule FDA-approved (Jain et al. 2017 ; Meiss et al. 2018 ) Sonidegib BCC Small molecule FDA-approved (Jain et al. 2017 ; Meiss et al. 2018 ) Glasdegib AML Small molecule FDA-approved (Norsworthy et al. 2019 ; Ribeiro et al. 2024 ) S1PR S1P Fingolimod TNBC, CRC (preclinical) Small molecule Repurposed (Rupp et al. 2021 ; Xie et al. 2025 ) GnRH-R GnRH Leuprolide/Goserelin/Degarelix Prostate cancer Peptide FDA-approved (Lappano and Maggiolini 2017 ; Fontana et al. 2020 ) SSTRs Somatostatin Octreotide/Lanreotide/ 1 ⁷⁷Lu-DOTATATE NETs Peptide/RLT FDA-approved (Pokuri et al. 2016 ; Hennrich and Kopka 2019a ) GPRC5D — Talquetamab Multiple myeloma Bispecific Ab FDA-approved (Lorente et al. 2025 ; Rodriguez-Otero et al. 2024 )

SMO inhibitors (Hedgehog pathway blockade)

Smoothened (SMO) is an oncogenic GPCR that functions as a key signal transducer in the Hedgehog pathway, driving tumor initiation, stemness, and therapeutic resistance in several cancers. While sonidegib has different pharmacokinetic and penetration profiles from vismodegib in locally advanced BCC, both agents showed an inhibition of the SMO 7TM pocket, reduced GLI‑dependent transcription, and achieved durable responses in HH‑addicted disease as shown in Fig. 5 (Michael Migden et al. 2021 ). However, their efficacy across most other solid tumors is limited due to frequent resistance via SMO drug‑binding pocket mutations (e.g., D473H/G), activation of downstream GLI2 amplification, SUFU loss, PI3K/MAPK pathway bypass, and the activation of HH‑independent GLI (Peer et al. 2019 ; Zhang et al. 2018 ; Kapeni et al. 2025 ; Yauch et al. 1979 ). Emerging evidence indicates that Smoothened (SMO) can also exhibit non-canonical GPCR functions independent of GLI-mediated transcription. A recent study demonstrated that SMO regulates CD8⁺ cytotoxic T cell migration within the tumor microenvironment through a GPCR-dependent mechanism involving Gi protein coupling and RhoA activation, rather than canonical Hedgehog signaling. Both genetic and pharmacological inhibition of SMO significantly impair T cell infiltration into tumors, without affecting upstream Hedgehog ligands or downstream GLI transcription factors. Consistently, treatment with SMO inhibitors such as vismodegib and sonidegib reduces CD8⁺ T cell migration and accumulation within tumors.

These findings indicate that SMO inhibitors can suppress anti-tumor immunity by limiting cytotoxic T cell trafficking into the tumor microenvironment, providing a mechanistic explanation for the limited efficacy of SMO-targeting therapies in many solid tumors and highlighting an important clinical limitation of this therapeutic strategy (Kapeni et al. 2025 ).

In contrast, in hematological malignancies, SMO inhibition has demonstrated more favorable clinical outcomes. For the newly diagnosed acute myeloid leukemia (AML), glasdegib (small‑molecule antagonist) with low‑dose cytarabine was approved by the FDA in 2018, which targets leukemic stemness and HH signaling in hematologic contexts by GLI downstream or parallel pathway activation with class‑typical resistance mechanisms downstream of SMO (Norsworthy et al. 2019 ; Ribeiro et al. 2024 ).

Moreover, itraconazole, an approved antifungal, has entered oncology trials for basal cell carcinoma (BCC), prostate cancer, and non-small cell lung cancer (NSCLC), including activity against SMO resistance mutants (SMO-D473H) in preclinical systems that cause resistance to other SMO antagonists, such as vismodegib and sonidegib (Wahid et al. 2016 ). Furthermore, itraconazole in Hodgkin-Huxley (HH) ‑relevant models and early trials binds a distinct SMO site and shows Hedgehog pathway blockade and anticancer activity; however, cellular readouts of SMO inhibition may not align with G‑protein signaling assays, and an integration with GLI/BRD4‑directed combinations should be considered represented in Table 2 and Fig. 6 (Kim et al. 2010 ). Fig. 6 Landscape of GPCR-targeted therapeutics across clinical development stages. This circos plot illustrates the clinical development status of therapeutic agents targeting specific G protein-coupled receptors (GPCRs)

Chemokine receptor–targeting strategies

Chemokine receptors contribute to cancer progression by regulating tumor cell migration, metastatic homing, immune evasion, and interactions with the tumor microenvironment, making them attractive therapeutic targets (Lorente et al. 2025 ). The defucosylated anti-CCR4 antibody mogamulizumab is FDA-approved for the treatment of certain cutaneous T-cell lymphomas (CTCL), including mycosis fungoides (MF) and Sézary syndrome (SS) (Ollila et al. 2019 ). In parallel, the bispecific antibody talquetamab has shown clinical utility in late-stage multiple myeloma (Fig. 6 ) (Mohty et al. 2011 ). Beyond these, additional repurposing opportunities have emerged through the antagonism of CXCR4 (fusin/CD184).

The best-known example is plerixafor, which disrupts CXCL12-mediated tumor retention. Plerixafor was approved by the FDA in 2008, in combination with granulocyte-colony stimulating factor (G-CSF), to mobilize hematopoietic stem cells in patients with non-Hodgkin’s lymphoma and multiple myeloma (Sison et al. 2014 ). Mechanistically, plerixafor blocks the SDF-1/CXCR4 axis, thereby preventing malignant cell survival within protective niches, mobilizing tumor cells into circulation, and improving accessibility to chemotherapy and immunotherapy, with extensive preclinical efficacy reported (Keating 2011 ; Rashidi and DiPersio 2016 ).

CXCR4 antagonism: Clinical trials have demonstrated the efficacy of plerixafor in combination with cytotoxics or immune checkpoint blockades (PD-1/PD-L1 inhibitors) in AML and in solid tumors with bone marrow niches or CXCL12-mediated immune exclusion (Fig. 7 ) (Morland et al. 2020 ). Importantly, optimal clinical translation may benefit from the incorporation of CXCR4 expression profiling and imaging biomarkers (Martin et al. 2021 ). However, compensatory signaling through alternative chemokine receptors such as ACKR3/CXCR7 and broader chemokine networks necessitates rational combination strategies and careful dose scheduling to maintain on-target efficacy (Smit et al. 2021 ). Fig. 7 GPCR targets across cancer types by ligand axis. Bubble plot showing GPCR targets (y-axis) implicated across multiple cancer types (x-axis), organized by major ligand axes (top). Each circle denotes an association between a GPCR–ligand axis and a specific cancer type. Circle color indicates regulatory or clinical development status (e.g., approved, clinical, preclinical), while circle size reflects the number of reported indications or supporting studies

CCR4 targeting: The defucosylated IgG1 antibody mogamulizumab is an FDA-approved GPCR-targeting therapy in adult T-cell leukemia/lymphoma (ATLL) and cutaneous T-cell lymphoma (CTCL) (Table 2 and Fig. 6 ) (Subramaniam et al. 2012 ). Beyond direct tumor debulking, mogamulizumab mediates tumor microenvironment (TME) modulation via receptor antagonism and antibody-dependent cell-mediated cytotoxicity (ADCC) against both CCR4 + malignant T cells and regulatory T cells (Tregs) (Choi et al. 2025 ). While mogamulizumab effectively targets cancer by depleting T-regulatory cells (Tregs), this mechanism can also contribute to immune-related side effects. Moreover, resistance may develop when cancer cells lose or downregulate the target antigen or otherwise adapt to the altered immune environment (Silva et al. 2024 ). However, many patients with SS and MF have developed resistance to mogamulizumab due to the L21V mutation in CCR4, which impairs the binding affinity of mogamulizumab. According to recent structural work by Choi et al. ( 2025 ), at position 21, the original amino acid (leucine) is replaced by valine, which is slightly smaller and therefore does not properly occupy the binding pocket. In addition, valine has a β-branched methyl group that causes steric interference with the surface of the binding pocket. Both of these features disrupt key interactions involving nearby residues (Y19 and E23) and prevent the antibody from forming a tight bond, resulting in reduced structural complementarity at the antibody–epitope interface. Consequently, this impairs stable antibody engagement and reduces the efficacy of mogamulizumab in antibody-dependent cellular cytotoxicity (ADCC) (Choi et al. 2025 ).

CCR5 inhibition: Other chemokine receptor strategies include maraviroc, originally approved for HIV therapy, which targets CCR5 (Ryst 2015 ). C–C chemokine receptor type 5 (CCR5), one of the GPCR receptors that is expressed on several immune cells [eosinophils, dendritic cells, macrophages, and T cells], can bind to multiple chemokines, including CCL3, CCL4, and CCL5. CCR5 undergoes a conformational change that activates intracellular signaling through dissociation of G-protein subunits, leading to activation of pathways such as phospholipase C, increased intracellular calcium, protein kinase C, and inflammatory gene expression, which play a crucial role in inflammation, immune cell trafficking, and mediate immune cells' physiological functions. Furthermore, CCR5 stimulates the PI3K–PDK1–AKT signaling axis, promoting cellular processes, such as protein synthesis, metabolism (glycolysis), survival, proliferation, and enhancing cellular migration, which are normally active in immune cells. However, in many types of cancers, CCR5 is pathologically overexpressed, consequently changing cells' homing behavior, motility, and altering gene expression. Cancer cells become highly responsive to chemokine gradients, leading them to migrate toward distant tissues and metastasis. Furthermore, CCR5 stimulates the PI3K–PDK1–AKT signaling axis, promoting cellular processes such as protein synthesis, metabolism (glycolysis), survival, proliferation, and enhancing cellular migration, which are normally active in immune cells. However, in many types of cancers, CCR5 is pathologically overexpressed, consequently changing cells' homing behavior, motility, and altering gene expression. Cancer cells become highly responsive to chemokine gradients, leading them to migrate toward distant tissues and metastasis. In other words, tumor cells actively migrate to specific distant organs, and not only promote homing to metastatic locations by following chemokine signals such as CCL5 produced in distant tissues, but also produce ligands such as CCL3, CCL4, and CCL5 to augment a proinflammatory, metastasis-promoting immune phenotype by shifting the tumor microenvironment toward tumor-supportive immune activity via simultaneously recruiting immunosuppressive cells, including regulatory T cells (Tregs), myeloid-derived suppressor cells (MDSCs), and tumor-associated macrophages (TAMs), into the tumor microenvironment, thereby allowing cancer cells to evade cytotoxic T-cell attack (Jiao et al. 2019 ; Pervaiz et al. 2019 ; Casagrande et al. 2018 ; Zhuang et al. 2021 ). Thus, CCR5 inhibition drugs such as small-molecule CCR5 antagonists (maraviroc and vicriviroc), as well as the humanized monoclonal antibody leronlimab, have been used as a therapeutic strategy to reverse these effects to reprogram the tumor microenvironment and disrupt tumor-promoting signaling. In addition, CCR5 inhibition can induce PD-L1 expression on tumor-associated cells, thereby priming immunologically “cold” tumors into hot tumors via reprogramming the tumor microenvironment to be responsive to immune checkpoint blockade. However, immune suppression will still persist because PD-L1 has an inhibitory effect on T-cell activity. Subsequently, a pairing step must be followed by adding PD-1/PD-L1 immune checkpoint inhibitors, such as pembrolizumab, to block PD-1/PD-L1 signaling and restore T-cell–mediated cytotoxic activity and enhance antitumor immune responses. This supports the “prime and pair” therapeutic paradigm, which represents a promising future direction in GPCR-targeted cancer therapy (Liu et al. 2025 ).(Pervaiz et al. 2019 ; Casagrande et al. 2018 ; Zhuang et al. 2021 ) While clinical translation in oncology remains limited, early studies suggest potential in CCL5/CCR5-high tumors, provided that robust biomarker stratification is required (Halvorsen et al. 2016 ; Huang et al. 2020 ).

Several new investigational drugs, including multiple clinical‑stage CXCR4 antagonists and antibodies that block the CXCR4 protein, are currently in clinical trials, such as taladegib, a SMO inhibitor with activity against resistance mutations (e.g., D473H), LEQ‑506, TAK‑441, BMS‑833,923, PF‑5,274,857, AZD8542, CUR‑61,414, IPI‑926, and MRT‑92 (acylguanidine class) with multi‑site SMO binder retaining activity versus SMO‑D473H has demonstrated favorable preclinical pharmacokinetics and efficacy (Maher et al. 2025 ; Goldman et al. 2015 ; Siu et al. 2501 ; Rohner et al. 2012 ; Mejía-Rodríguez et al. 2023 ; Tang et al. 2011 ; Jamieson et al. 2020 ; Hoch et al. 2015 ).

Beyond existing therapies, motixafortide represents a significant advancement as a novel, high-affinity peptide antagonist of CXCR4, superior to earlier agents like plerixafor. Motixafortide received FDA approval in September 2023 for use in multiple myeloma in combination with filgrastim to mobilize hematopoietic stem cells into the peripheral blood for collection and subsequent autologous transplantation. Results from the GENESIS Phase 3 trial demonstrated that the combination of motixafortide and filgrastim enabled a significant majority of patients, particularly hard-to-mobilize patients, to reach the target collection of \documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$$\ge 6\times {10}^{6}$$\end{document} CD34 + cells/kg in just one apheresis session (Crees et al. 2023a ).

A related area of active research is the development of theranostics for imaging and therapy, especially in hemato‑oncology(Weber et al. 2023 ). Diagnostics CXCR4 PET tracers are not approved therapies; however, CXCR4‑targeted RLT shows clinical activity and myeloablation in refractory lymphomas but remains investigational (Buck et al. 2023 ).

Other GPCR modulators with oncologic impact

Other agents, such as fingolimod and other related sphingosine 1-phosphate receptor (S1PR) modulators, which are approved for multiple sclerosis (MS) and ulcerative colitis (UC), have also shown anti-tumor effects in triple-negative breast cancer preclinical models and colorectal cancer models through lymphocyte sequestration. However, their use in oncology still requires caution before moving into clinical practice (Rupp et al. 2021 ; Xie et al. 2025 ).

In addition, established endocrine or neuroendocrine GPCR therapies remain core precedents. For example, GnRH receptor modulators such as leuprolide and goserelin (agonists) and degarelix (antagonist) are widely used in prostate cancer to suppress androgen production via GnRH-R modulation and exhibition of direct anti-proliferative and pro-apoptotic effects(Lappano and Maggiolini 2017 ; Fontana et al. 2020 ). In addition, somatostatin receptor-targeted therapies (e.g., lanreotide and octreotide) and radioligand therapies such as the FDA-approved Lutathera (177Lu-DOTATATE) have proven effective in well-differentiated neuroendocrine tumors (NETs) that express somatostatin receptors (Pokuri et al. 2016 ; Hennrich and Kopka 2019a ).

Emerging and combination treatments

SMO inhibitors are potent in HH‑addicted tumors genomically, but their efficacy as single agents in other cancers is limited due to frequent resistance and activation of downstream or parallel pathways (Atwood et al. 2015 ). In addition, SMO inhibition may reduce intertumoral CD8⁺ T-cell migration through RhoA-dependent noncanonical SMO signaling in T cells, with implications for combinations with immunotherapy (Kapeni et al. 2025 ). For chemokine receptor–targeted strategies such as CXCR4 and CCR5, therapeutic benefit is often restricted by pathway redundancy (e.g., CXCR4–ACKR3 cross-talk) and tumor microenvironment (TME) compensation (Ridley and Dyer 2022 ). This underscores the need for combination approaches and biomarker-guided deployment to maximize effectiveness.

Resistance to SMO inhibitors frequently develops through several mechanisms, including on-target SMO binding pocket mutations, downstream alterations in GLI2 or SUFU, and pathway bypass via PI3K/MAPK signaling (Zhang et al. 2018 ; Piteša et al. 1353 ). Nevertheless, alternative SMO ligands such as itraconazole or the second-generation posaconazole (Zhang et al. 2018 ), as well as combination approaches targeting downstream or parallel pathways (e.g., BRD4, MEK, PI3K) (Tiago et al. 2020 ; Zhang et al. 2021 ), are active areas of investigation. However, noncanonical SMO inhibition may also reduce CD8⁺ T-cell infiltration into tumors via RhoA signaling, which has several safety issues, including muscle cramps, dysgeusia, and alopecia as common adverse events(Polizio et al. 2011 ; Wu et al. 2023 ).

Nilotinib, a receptor tyrosine kinase (RTK) inhibitor, has also been reported to exhibit off-target SMO binding, in which many computational and experimental data suggest it has a stronger suppression of GLI1 and tumor growth than vismodegib in HH-dependent medulloblastoma and glioblastoma xenograft models (Chahal et al. 2019 ). Thus, suggesting the value of polypharmacology, including SMO antagonism, where dual targeting of RTKs and SMO could provide therapeutic benefit. Nevertheless, class-typical SMO resistance mechanisms are expected to remain relevant in HH-dependent tumors (Nguyen and Cho 2022 ).

Systemic blockade of CXCR4 disrupts both hematopoiesis and immune cell trafficking but is generally well tolerated (Singh et al. 2020 ; Mezzapelle et al. 2314 ). Its efficacy may be enhanced with rational combinations between chemotherapy and PD-1/PD-L1 immune checkpoint blockade therapy (chemo/PD‑1 axis) (Chen et al. 2021 ). In addition, biomarker-guided approaches, such as CXCR4-targeted imaging, can help identify tumors with high CXCR4 expression and guide therapeutic intervention. Expert consensus highlights that CXCR4 imaging demonstrates both anti-lymphoma activity and myeloablative effects in refractory cases, underscoring not only the potency of targeting this axis but also the associated risks of systemic inhibition (Buck et al. 2023 ).

GPCRs as actionable biomarkers in cancer

Across multiple cancer models discussed, the expression of G protein-coupled receptors (GPCRs) is considered to be cancer-type-specific, supporting their potential to serve as diagnostic, prognostic, and predictive markers. As shown in Table 1 , the abnormal expression of GPCRs, including EP4, PAR1, CXCR4, ETAR, GRPR, and lysophosphatidic acid receptors (LPARs), reflect tumor progression and invasiveness in multiple cancers such as colorectal, breast, prostate, ovarian, lung, and pancreatic cancers. Activation of GPCR-associated signaling pathways, such as β-catenin, MAPK/PI3K cascades, receptor tyrosine kinase transactivation, and Hedgehog–SMO signaling, indicates tumor aggressiveness. Furthermore, assessing specific ligand-receptor axes, such as CXCL12/CXCR4, CCL5/CCR5, PGE₂/EP receptors, and GRP/GRPR, allows the capture of critical aspects of tumor–microenvironment crosstalk, immune modulation, and metastatic potential, further reinforcing their potential as functional biomarkers. Ligand receptor axes with their corresponding GPCR targets and tumor-associated are represented in Fig. 7 (Morland et al. 2020 ; Smit et al. 2021 ; Huang et al. 2022 ).

Notably, in clinical practice, several GPCR-related biomarkers have been used in diagnosis or GPCR-targeted therapy. For instance, somatostatin receptor expression in neuroendocrine tumors, SMO pathway dependency in Hedgehog-driven malignancies, and chemokine receptor expression (such as CXCR4 and CCR4) in hematologic and selected solid tumors (Lorente et al. 2025 ; Pokuri et al. 2016 ; Poeta et al. 2019 ). These specific expression patterns and signaling of the GPCRs are considered as actionable molecular therapeutic markers for patient stratification and treatment choices. Kinase inhibitors have historically dominated targeted therapies in oncology, and many clinical efforts have exploited GPCRs in therapy. The approval of Smoothened (SMO) inhibitors between 2012 and 2018 for Hedgehog-driven basal cell carcinoma and acute myeloid leukemia has initiated a shift in demanding GPCRs targeted therapy to be in clinical practice. Considerably, SMO, a class F (Frizzled) GPCR, is a central component of Hedgehog signaling, a pathway whose aberrant activation is estimated to contribute to increased cancer-related mortality. Several additional SMO-targeting agents are currently undergoing late-stage clinical evaluation (Lorente et al. 2025 ).

Beyond SMO, chemokine receptors have emerged in clinical practice as potential therapeutic targets due to their roles in tumor-associated inflammation, immune evasion, and resistance to therapy. In particular, the CCR4-targeting monoclonal antibody mogamulizumab is approved for the treatment of mycosis fungoides and Sézary syndrome. Also, ongoing clinical trials are exploring chemokine receptor inhibitors in combination with chemotherapy or antibody-based regimens. More recently, the multiple myeloma treatment talquetamab, a first-in-class bispecific GPRC5D–CD3 T-cell engager, was approved in 2023. Its properties as a bispecific antibody (BsAb) allow it to bind to CD3 on the T cells and to GPRC5D on multiple myeloma (MM) plasma cells and form an immune synapse, which utilizes high GPRC5D expression to selectively direct T-cells to specifically kill tumor cells, and ongoing trials are exploring its use following BCMA-directed CAR T-cell therapy (Lorente et al. 2025 ; Rodriguez-Otero et al. 2024 ). Notably, GPRC5D is a G protein-coupled receptor (GPCR), specifically its gene, located on chromosome 12 (12p13), and is part of the Class C GPCR family, with an extracellular amino-terminal domain (ATD) of approximately 30–50 amino acids, in contrast to the extended ATDs of ~ 500–600 amino acids that are observed in this receptor family. This reduced extracellular architecture positions the antigenic epitope of GPRC5D in close proximity to the plasma membrane, which has important functional implications for therapeutic targeting, allowing a spatial configuration that enhances T-cell activation and promotes effective cytotoxic responses mediated by perforin and granzyme release, thereby improving tumor cell killing (Chari et al. 2022 ).

However, toxicity characterization, especially for GPRC5D-associated on-target/off-tumor effects, is important to assess, as GPRC5D is also expressed in normal tongue epithelium, skin (hair follicles/glands), and nails. To highlights both the efficacy and the distinctive toxicity profile associated with GPRC5D targeting, here is a direct comparison between the Phase 1/2 MonumenTAL-1 trial and a recent real-world multicenter analysis of talquetamab in relapsed/refractory multiple myeloma (RRMM), which highlights both the consistency in efficacy and the distinctive toxicity profile associated with GPRC5D targeting. In MonumenTAL-1, talquetamab demonstrated overall response rates (ORR) of approximately 64% with a biweekly subcutaneous dose (0.8 mg/kg) in heavily pretreated patients (Chari et al. 2025 ). In comparison, the real-world cohort of 114 patients exhibited a similarly high ORR of 73%. talquetamab’s anti-myeloma efficacy in both clinical trial and real-world populations was high even when patients are more refractory and higher risk (Al Hadidi et al. 2025 ).

On the other hand, talquetamab shows multiple adverse effects, particularly dysgeusia, progressive weight loss, and ectodermal manifestations cause of GPRC5D expression in normal cells. For instance, in the MonumenTAL-1 trial, talquetamab demonstrated a cytokine release syndrome (CRS) occurring in approximately 73–79% of patients, predominantly of grade 1–2 severity, dysgeusia was reported in approximately 70–76% of patients across all treatment groups, infections occurred in approximately 60–75% of patients, and hematologic toxicities were frequent, including grade 3–4 neutropenia (21–47%), anemia (26–31%), and lymphopenia (17–26%). However, fatal adverse events were rare and not treatment related (Chari et al. 2025 ). In the real-world multicenter study reported lower observed rates of these adverse events, including CRS (54%) and infections (27%, with 18% grade ≥ 3), were reported, suggesting potential differences in patient monitoring, reporting practices, and supportive care strategies outside of clinical trials. However, despite lower reported infection rates, more than half of infections required hospitalization, highlighting their clinical significance. While dysgeusia and related mucosal toxicities were not systematically captured in the real-world dataset, their downstream clinical manifestation, progressive weight loss reaching approximately 8.8% at 6 months, will limit treatment continuity and affect the quality of life (Al Hadidi et al. 2025 ).

Precision medicine and molecular imaging in GPCR-targeted oncology

GPCRs, as conventional biomarkers, showed considerable limitations due to receptor expression heterogeneity within tumors, which leads to inaccurate patient diagnosis in early stages. Modern molecular imaging relies on highly sensitive techniques such as Single Photon Emission Computed Tomography (SPECT) and Positron Emission Tomography (PET) to detect the interaction between a radiolabeled probe and a specific biological target in the body. This radioprobe is designed to bind selectively to a target, such as GPCR receptors that are overexpressed on tumor cells, then the radionuclide emits detectable radiation that can be captured via PET or SPECT. Therefore, molecular imaging provides a powerful solution to this challenge by enabling patient-specific, non-invasive, whole-body assessment of receptor expression in vivo. GPCRs have high cell-surface density (typically 10 3 –10 4 receptors per cell), and their natural capacity to internalize after binding to a ligand allows imaging agents and therapeutic compounds to be efficiently taken up and retained within cells. The detected signals are then reconstructed into quantitative images that reflect the precise localization and characterization of the target molecule, even in cancers that may have high heterogeneity, and are considered a non-invasive assessment at the molecular and cellular level that captures the target molecule's expression and activity, and also biological processes like apoptosis and angiogenesis. This high sensitivity makes PET and SPECT essential tools for precision medicine, enabling early diagnosis, identification of metabolic changes prior to anatomical manifestations, staging, assessment of drug pharmacodynamics, and pharmacokinetics (Ahmadzadehfar and Essler 2018 ; Machado et al. 2019 ).

Building on this diagnostic capability, nuclear medicine has developed the concept of theranostics, which has a dual function integrating diagnosis and treatment using the same or closely related molecular agents, by attaching different types of radioactive isotopes (radionuclides) or by adjusting the administered dose. This dual functionality is achieved in two phases: (i) the diagnostic phase, where targeting molecules are labeled with a radionuclide suitable for imaging, such as a gamma-emitting isotope or positron-emitting isotope, and images are captured once they bind to their specific target in vivo, which serves as a biomarker. (ii) In the therapeutic phase, the same targeting molecule is labeled with a beta-emitting radionuclide, such as lutetium-177 or yttrium-90. They emit localized radiation at the binding site to destroy cancer cells, which directly damages the tumor cells and minimizes off-tumor toxicity (Machado et al. 2019 ; Li et al. 2017 ).

For instance, PentixaFor molecules serve as the targeting vector that binds specifically to the CXCR4 receptor, functioning as a diagnostic imaging agent via its ⁶⁸Ga (Gallium-68) labeled (positron-emitting isotope) that is detected by PET imaging, allowing non-invasive visualization and quantification of CXCR4 expression. While using PentixaTher 1 ⁷⁷Lu (Lutetium-177) or ⁹⁰Y (Yttrium-90) labeled, the compound becomes a treatment agent. These isotopes emit high electron energy (β-particles) reaults in localized cytotoxic radiation damage, which is now targeting only the tumor cells that have high expression of CXCR4 (Buck et al. 2023 ). Furthermore, radiolabeled peptides aid theranostic peptide radiopharmaceuticals for better diagnosis and personalized treatment. NET patients have high expression of somatostatin receptors (SSTR2) in comparison to healthy individuals; thus, theranostics based on radiolabeled somatostatin analogs are used for imaging. Early SPECT-based agents include [Tyr 3 ]Octreotide (TOC) labeled with I-123, and OctreoScan labeled with In-111, and modern PET-based agents like 68Ga-DOTA-TATE, DOTA-TOC, and DOTA-NOC are used in the diagnosis phase.

While in the therapy phase, multiple radiolabeled agents were developed to increase response rate, quality of life, and lower toxicity profile, such as in beta-emitter therapy (standard PRRT) that uses 177Lu-DOTA-TATE, 177Lu-DOTA-TOC, 90Y-DOTA-TOC, and Cu-67, and in alpha-emitter therapy (new/emerging), 225Ac-DOTA-TATE, 225Ac-DOTA-TOC, and 212Pb-DOTAM-TATE. The efficacy is higher in targeted alpha therapy (TAT) than beta-emitter therapy, due to alpha particles’ linear energy transfer being high, which causes double-strand DNA breaks and rapid cell death; In addition, alpha particles have a range of about 2–3 cell diameters (50–100 µm), which is short, causing less surrounding damage to healthy cells (Nock et al. 2023 ; Hennrich and Kopka 2019b ; Eychenne et al. 2020 ).

Another example of using GPCRs in cancer theranostics is the Cholecystokinin-2 receptor (CCK2R), which is in the gut mucosa and stomach. This receptor is highly expressed in stromal ovarian tumors, medullary thyroid carcinoma (MTC), and gastrointestinal stromal tumors (GIST). The radioligands used to target these receptors are gastrin/CCK, in which their N-terminus is modified with chelators to stabilize binding with radioactive isotopes like [111In]In-DTPA-MG0, [111In]In-DOTA-MG11, [111In]In-DOTA-CCK, and [99mTc]Tc-DG2 for scintigraphy to CCK2R-expressing human tumors. In MTC theranostics, for example, [68Ga]Ga-MGS5 PET/CT has a high ability to detect lesions accurately, making it a promising option for patients with metastases and local recurrence (Guggenberg et al. 2023 ). The therapeutic theranostic agents that can be used are [177Lu]Lu-CP04 and [177Lu]Lu-PP-F11N. Clinically, [177Lu]Lu-PP-F11N showed high efficacy in treatment with low bone marrow and kidney radiation doses (Rottenburger et al. 2020 ).

Overall, in multiple human malignancies, receptor expression heterogeneity remains a major obstacle to early diagnosis and effective drug uptake. Therefore, there is a clear need to develop new approaches that provide reliable results, especially in early-stage, recurrent, or metastatic tumors, with precise localized targeting. In this context, radionuclides and radiopharmaceuticals used in cancer theranostics represent a highly promising clinical strategy, as they enable non-invasive, highly specific imaging along with efficient drug delivery and penetration into tumor tissues, which these approaches help select the right patients for therapy and improve the chances of treatment success (Gorica et al. 2023 ; Wiele et al. 2008 ). Figure 5 B shows therapeutic modalities of GPCR-targeting anticancer agents distribution across active clinical trial stages. For a full list of abbreviations, see the list of abbreviations Table 3 . Table 3 List of abbreviations Abbreviation Full name 4-OHT 4-Hydroxytamoxifen α-MSH α-Melanocyte Stimulating Hormone β-arr Beta-Arrestin AC Adenylyl Cyclase Akt Protein Kinase B AKT Protein kinase B Ang-II Angiotensin II AP-1 Activator Protein-1 APC Adenomatous Polyposis Coli AT1 Angiotensin II Receptor Type 1 ATF3 Activating Transcription Factor 3 B2R Bradykinin B2 Receptor B2R Bradykinin receptor B2 BAD Bcl-2-associated death promoter Bcl-2 B-cell lymphoma 2 BK Bradykinin cAMP cyclic Adenosine Monophosphate CAMP Cyclic adenosine monophosphate CARD10 Caspase recruitment domain family member 10 CCK Cholecystokinin Receptor CDC42 Cell division control protein 42 homolog CHK1 Checkpoint kinase 1 c-Jun Cellular Jun CMA Chaperone-mediated autophagy c-Myc Cellular Myelocytomatosis COPS8 COP9 signalosome complex subunit 8 COX-2 Cyclooxygenase-2 COX-2 Cyclooxygenase-2 CREB cAMP Response Element Binding protein CREB cAMP-responsive element-binding protein c-Src Cellular Sarcoma CTGF Connective Tissue Growth Factor CTGF Connective tissue growth factor CXCL C-X-C Motif Chemokine Ligand CXCL Chemokine (C-X-C motif) ligand CXCL8 (IL-8) Interleukin-8 CXCR C-X-C Motif Chemokine Receptor CXCR C-X-C chemokine receptor CXCR1/2 Chemokine receptors 1 & 2 DEPTOR DEP domain containing mTOR-interacting protein DNA-PK DNA-dependent protein kinase EDNRB Endothelin B receptor EGR1 Early Growth Response 1 EP Prostaglandin E2 Receptor EP4R EP4 Receptor ER Endoplasmic reticulum ErbB Human Epidermal Growth Factor Receptor ERK Extracellular Signal-Regulated Kinase ERK Extracellular signal–regulated kinase ET-1 Endothelin-1 ET1, ET2, ET3 Endothelin-1, −2, −3 ETAR Endothelin Type A Receptor ETBR Endothelin Type B Receptor F2 Thrombin FAK Focal Adhesion Kinase FAK Focal adhesion kinase FGFR Fibroblast Growth Factor Receptor FOS FBJ Murine Osteosarcoma Viral Oncogene Homolog FOXO Forkhead box O transcription factors FOXO1/3A Forkhead box O1/3a G12 G-proteins 12 GFAP Glial fibrillary acidic protein GI-RAS-MEKK1 G-Protein Inhibitory-Rat Sarcoma-Mitogen-Activated Protein Kinase Kinase Kinase 1 GPER1 G Protein-coupled Estrogen Receptor 1 GRK G protein–coupled receptor kinase GRP Gastrin-Releasing Peptide GRPR Gastrin-Releasing Peptide Receptor GRPR Gastrin-releasing peptide receptor GS Glutamine Synthetase GSK-3/GSK3Β Glycogen synthase kinase-3 beta GTP Guanosine-5′-triphosphate HIF-1α Hypoxia-Inducible Factor 1-alpha IGF-1R Insulin-like Growth Factor 1 Receptor IKKΑ IκB kinase alpha ILK Integrin-linked kinase JAK Janus kinase LEF Lymphoid Enhancer-Binding Factor LPA Lipoprotein (a) gene LPAR Lysophosphatidic Acid Receptor MAPK Mitogen-Activated Protein Kinase MAPK Mitogen-activated protein kinase MC1R The Melanocortin 1 Receptor MC1R Melanocortin 1 receptor MCAM Melanoma Cell Adhesion Molecule MCAM Melanoma cell adhesion molecule MITF Microphthalmia-associated Transcription Factor MLST8 Mammalian lethal with Sec13 protein 8 MMP Matrix Metalloproteinase MPTP Mitochondrial permeability transition pore MSIN1 Mammalian stress-activated protein kinase-interacting protein 1 mTOR Mechanistic Target of Rapamycin MTOR Mechanistic target of rapamycin MTORC1 Mechanistic target of rapamycin complex 1 NF-kB Nuclear Factor kappa-light-chain-enhancer of activated B cells PAR1 Protease-Activated Receptor 1 PGE2 Prostaglandin E2 PI3K Phosphoinositide 3-kinase PKA Protein Kinase A PKCd Protein Kinase C delta PLCβ Phospholipase C beta Pyk2 Proline-rich tyrosine kinase 2 RAF Rapidly Accelerated Fibrosarcoma RANKL Receptor Activator of Nuclear Factor Kappa-B Ligand RAS Rat sarcoma virus Rho Ras Homology ROCK Rho-associated Coiled-coil Kinase RUNX2 Runt-related transcription factor 2 STAT3 Signal Transducer and Activator of Transcription 3 TCF T-Cell Factor TGF Transforming growth factor TP53 Tumor Protein p53 VEGF Vascular Endothelial Growth Factor Wnts Wingless-related integration sites

Limitations of the study

Based on the current clinical evidence available, many of the GPCR-targeting therapies mentioned in this study are in the process of being investigated at the preclinical and early clinical stages of development, and the effectiveness, specificity, and safety profiles have yet to be confirmed. Furthermore, the combination treatment methods and potential resistance mechanisms suggested herein are based on pathway-level data and require clinical validation. As such, it would be premature to treat them as solid evidence that could guide the practice.

Furthermore, the stratification of patients poses another significant problem that is not satisfactorily solved in the course of our research. Although we emphasize the drawbacks of using fixed biopsies for the identification of biomarkers and suggest considering dynamic strategies, like molecular imaging, there are numerous issues related to inter- and intra-patient variability in terms of the expression of GPCRs. Therefore, further experimental validation and large-scale analyses will be required to fully realize the potential of GPCR-targeted strategies in precision oncology.

Conclusion

A deeper understanding of GPCR signaling at a more intrinsic level provides a strategic platform to redefine cancer biology and oncology therapy. These receptors represent dynamic regulators of communication between cells and their microenvironment, and their aberrant signaling is a central driver of malignancy. Comprehension of their structural and functional mechanism allows scientists to define actionable molecular targets and repurpose GPCR modulators as oncology therapeutics. Converting this knowledge from molecular insight to therapeutic use will be crucial to creating selective, efficient, and less toxic therapies in cancer treatment.

The approved FDA GPCR-targeted drugs, including SMO inhibitors, antagonists of chemokine receptors, and modulators of endocrine receptors, have a significant clinical efficacy but in specific cancer types, such as basal cell carcinoma, hematologic malignancies, and neuroendocrine tumors. The limitation of these drugs to specific cancer types is due to the tumor resistance mechanisms, pathways bypass, and microenvironment adaptation. However, a highly effective therapeutic approach in the development of GPCR-targeted agents is the implementation of combination treatment strategies, which are essential for maximizing both the long-term efficacy and pharmacological selectivity and reducing potential side effects of these drugs.

The most challenging aspect in targeted medicine is the limitation of GPCR biomarker assessment due to tumor heterogeneity and impediments in patients’ early diagnosis, which has led to the rise of non-invasive, targeted, and therapeutic approaches. Thus, molecular imaging and precision theranostics therapy are considered the future actionable clinical perspective. Collectively, the present work advances the field by offering a mechanistic, multi-layered, and clinically actionable perspective that bridges GPCR biology with precision oncology.

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Acknowledgements

We would like to acknowledge the Faculty of Science, Port Said University, and Department of Pharmacology and Therapeutics, United Arab Emirate University for their contributions to the study.

Authors’ contributions

SA performed the literature review and served as the lead author of the manuscript. ME interpreted information regarding chemokine receptor targeting in oncology. All authors contributed to the final revision and approved the final manuscript.

Data availability

No datasets were generated or analysed during the current study.

Declarations

Ethics approval and consent to participate

Not applicable.

Consent for publication

Not applicable.

Competing interests

The authors declare no competing interests.

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