Targeting tumor-associated G-protein coupled receptors: beyond single-axis inhibition toward multidimensional regulation.

Despite significant progress in developing GPCR-targeted anti-tumor agents, their clinical translation faces three core challenges related to target complexity, technological limitations, and clinical translation barriers [ 141 ]. Viewing these challenges within the context of the TME reveals three interconnected categories that help explain why even well-validated GPCR targets frequently fail to produce durable clinical responses. First, the functional pleiotropy of GPCR signaling networks across different TME compartments represents a central difficulty in drug development. The same receptor can exert diametrically opposed effects within distinct cellular contexts; for instance, β2-AR agonists may promote tumor proliferation in cancer cells while simultaneously activating anti-tumor immune responses [ 142 ]. This bidirectional nature complicates efficacy prediction. Furthermore, tumor heterogeneity exacerbates this challenge. Dynamic expression differences in GPCR subtypes across tumor cell subpopulations (e.g., receptor upregulation induced by microenvironmental changes) render single-target agents inadequate for eradicating all malignant cells [ 143 , 144 ]. The continual emergence of novel targets also increases developmental complexity. Recent research revealed that failure of glutamine competition within the liver cancer microenvironment activates the IRE1α/XBP1 signaling pathway in myeloid cells, inducing aberrant expression of the immunosuppressive receptor GPR109A, thereby establishing it as a putative immunometabolic checkpoint target [ 145 ]. Second, the adaptive and compensatory nature of GPCR signaling networks creates a moving target for therapeutic intervention. Even when a receptor is successfully inhibited, tumor cells often activate parallel pathways to circumvent the blockade—a phenomenon well-documented for SMO inhibitors, where resistance emerges through downstream pathway reactivation or receptor mutations^67^. This network-level plasticity means that static, single-agent approaches are inherently vulnerable to eventual therapeutic escape. Third, the physical and immunological barriers of the TME pose formidable delivery challenges [ 146 ]. The blood-brain barrier (BBB) exemplifies this problem, as >98% of small molecules and antibody therapeutics fail to cross it effectively, contributing to treatment failures in CNS tumors like gliomas. Beyond the BBB, dense stromal architecture, abnormal vascularization, and immunosuppressive cell infiltrates collectively limit drug penetration and activity within solid tumors. Designing effective GPCR-mediated transport systems capable of traversing the BBB represents one of the most pressing technical challenges currently demanding solutions. At the molecular level, these clinical challenges are rooted in fundamental knowledge gaps. The conformational dynamics (e.g., active/inactive state transitions) and membrane-embedded nature of GPCRs significantly increase the difficulty of obtaining high-resolution structural data [ 147 , 148 ]. Although cryo-electron microscopy (cryo-EM) has accelerated structural biology advances (e.g., elucidating the conformational transition mechanism of aGPCR-CD97), substantial gaps remain in the structural understanding of orphan receptors, low-abundance GPCRs, or specific functional states (e.g., biased signaling complexes), hindering structure-based rational drug design [ 149 ]. Furthermore, the high conservation of TMDs among GPCR family members (e.g., >80% homology in Class A) often leads to off-target effects for orthosteric site inhibitors (e.g., vismodegib side effects). From a clinical translation perspective, the off-target toxicity represents a prominent concern. Given the ubiquitous expression of GPCRs in normal tissues (e.g., cardiovascular and nervous systems), early-developed agonists often failed in clinical trials due to cardiovascular side effects, underscoring the critical importance of precise targeting. Furthermore, the pleiotropic signaling of GPCRs and tumor heterogeneity considerably complicate efficacy prediction in clinical applications, elevating both the risks and costs associated with clinical trials. Addressing the multifaceted challenges outlined above requires an equally multidimensional technological response [ 150 , 151 ]. The rapid advancement of artificial intelligence (AI) and computational biology is injecting robust momentum into this field, offering novel breakthroughs to address these bottlenecks [ 152 ]. Deep learning-driven virtual screening techniques are efficiently identifying ligands for GPCR allosteric sites, significantly accelerating the discovery of lead compounds. Yan Li et al. successfully identified 15 bioactive compounds exhibiting β-AR antagonist activity using fragment-based computational screening [ 153 ]. Pan et al. determined the high-resolution cryo-EM structure of the HCAR1-Gi1 protein complex, not only revealing the precise molecular mechanism of HCAR1-mediated signal transduction but also establishing a crucial structural foundation for developing novel HCAR1-targeted anti-tumor drugs [ 154 ]. Dynamic conformational prediction techniques can simulate the dynamic transitions between GPCR active and inactive states, guiding the design of highly specific drugs to mitigate off-target effects. Concurrently, breakthroughs in cryo-EM are accelerating the process of obtaining high-resolution GPCR structures. A team led by Shandong University and Zhejiang University, employing cryo-EM combined with cellular functional assays and molecular dynamics simulations, unveiled the first structures of the aGPCR CD97 in both inactive and active states, elucidating its mechanosensitive activation mechanism (force-sensing) and providing critical information for future drug discovery [ 155 ]. Such high-precision structural information underpins structure-based drug design, substantially enhancing the efficiency and success rate of drug development. Exemplifying this, the Lu team leveraged reported crystal structures of the EP4 receptor for molecular design; the resulting lead EP4 antagonist, compound 14, exhibited 20-fold greater potency than the clinical molecule E7046, achieving an IC50 of 1.1 nM [ 156 ]. This case underscores the immense value of structural information in optimizing drug efficacy. AI-driven tools like AlphaFold demonstrate high accuracy in predicting GPCR structures, offering a path forward for receptors that remain structurally uncharacterized. Building on an AlphaFold-generated GPRC5D model, its complex structure with an scFv was determined via cryo-EM, revealing unique dimerization and antibody-binding epitopes [ 157 ]. This work not only deepens understanding of this target but also provides crucial structural insights for developing antibody-based therapeutics against MM. Concurrently, high-throughput screening technologies are being enhanced through tumor organoid models, whose 3D culture systems effectively recapitulate TME complexity. Automated microfluidic platforms, enabling dynamic drug delivery and real-time monitoring, open new avenues for validating the synergistic mechanisms of GPCR-targeted combination therapies, thereby supporting more precise drug evaluation [ 158 ]. Innovative screening approaches, like combining independent protein-SELEX (systematic evolution of ligands by exponential enrichment) and cell-SELEX with bioinformatics-driven prioritization, may identify high-affinity aptamers, overcoming traditional screening limitations [ 159 ]. This methodology holds promise for overcoming limitations inherent in traditional screening methods, offering a new paradigm for discovering highly efficient and specific tool molecules or potential therapeutic agents targeting GPCRs. Advanced genomic technologies, including whole-genome sequencing (WGS), single-cell copy number variation sequencing (scCNV-seq), and single-cell RNA sequencing (scRNA-seq), helped elucidate resistance mechanisms, as demonstrated in studies of antigen escape following BCMA- or GPRC5D-targeted immunotherapy in MM [ 160 ]. Their study revealed that genomic events, such as biallelic loss, missense mutations, and in-frame deletions affecting either the BCMA or GPRC5D genes, emerged in a subset of patients post-treatment. These alterations enabled tumor cells to resist immune-mediated targeting pressure. These findings underscore the pivotal role of single-cell genomics and bioinformatics in understanding therapy escape and provide crucial foundations for designing next-generation agents and optimizing regimens. Together, these advances represent not incremental progress but a fundamental shift in our capacity to engage GPCR complexity. By enabling the design of context-aware therapeutics capable of anticipating resistance, overcoming physical barriers, and selectively modulating distinct cell types within the TME, they chart a path toward the ultimate goal of multidimensional TME remodeling.

GPCR-targeted cancer therapy has arrived at a pivotal juncture. For decades, the field has been guided by a compelling yet incomplete consensus: that GPCRs, as the largest and most pharmacologically tractable family of membrane proteins, hold immense promise for oncology [ 161 ]. This promise has been realized for a select subset of targets, yielding approved agents that have benefited patients with neuroendocrine tumors, hormone-dependent malignancies, and hematological cancers. Nevertheless, the vast majority of tumor-associated GPCRs remain therapeutically untapped, and even established therapeutics ultimately confront resistance. The central thesis of this review is that this translational gap stems not merely from technical limitations in ligand development, but from a conceptual constraint inherent in how the role of GPCRs in cancer has traditionally been framed. The prevailing paradigm of single-axis inhibition is epitomized by orthosteric ligands designed to simply activate or block receptor function. This approach is fundamentally misaligned with the biological complexity of GPCR signaling within the TME. As delineated throughout this review, GPCRs are not static switches but dynamic nodes that integrate inputs across diverse cell types, adapt to contextual cues, and engage compensatory networks. A single receptor may drive proliferation in malignant cells while concurrently recruiting immunosuppressive populations; a pathway ostensibly inhibited by a small molecule may be reactivated through parallel signaling axes; a target successfully engaged in the peripheral circulation may prove inaccessible within the dense stromal architecture of a solid tumor. These phenomena are not exceptional outliers but rather inherent features of GPCR biology in the TME, features that collectively define the “multidimensional regulatory conundrum” this review has sought to elucidate. This complexity, far from justifying therapeutic nihilism, instead provides the conceptual bedrock for designing more sophisticated interventions. The emerging modalities surveyed herein share a unifying objective: to transcend conventional receptor blockade and enable active, context-aware intervention within the TME ecosystem [ 162 ]. Allosteric modulators afford pathway-selective regulation, disentangling therapeutic from detrimental signaling. Protein degraders eliminate the target protein entirely, outmaneuvering adaptive resistance mechanisms. Nucleic acid technologies intervene at the transcriptional level, addressing aberrant GPCR expression at its source. Cellular therapies transform lymphocytes into living therapeutics capable of sensing, trafficking to, and remodeling the TME while executing cytotoxic functions. Each of these approaches, in its distinct manner, embodies the conceptual transition from single-axis inhibition to multi-dimensional regulation. Critically, this therapeutic evolution is being propelled by parallel advances in foundational technologies. Artificial intelligence and computational biology are demystifying GPCR structural dynamics, revealing allosteric pockets and conformational states that were previously inaccessible. Cryo-electron microscopy is yielding high-resolution structures of historically intractable targets, including aGPCRs and their signaling complexes. Organoid models and microfluidic platforms are recapitulating TME complexity ex vivo, enabling more physiologically predictive drug evaluation. Single-cell genomics is tracing the evolutionary trajectories of therapeutic resistance in real time, informing rational combination strategies. These enabling technologies are not merely ancillary, but are fundamentally redefining the feasible landscape of GPCR drug discovery. Looking forward, the central challenge is no longer the identification of additional GPCRs with oncological relevance, but rather the determination of how best to engage each receptor within its specific TME context. This endeavor will necessitate the integration of structural, functional, and spatial information to design therapeutics that are not only potent and selective, but also context-aware and evolutionarily resilient [ 163 ]. For some targets, optimal engagement may involve biased ligands that preferentially activate beneficial signaling pathways while sparing those associated with adverse effects. For others, it may entail degraders that preempt resistance by effecting complete target elimination. For receptors selectively expressed on malignant cells, CAR-based cellular therapies may prove most effective. For those embedded within stromal or immune compartments, allosteric modulators capable of fine-tuning receptor signaling may be preferable to agents that simply ablate it. In summary, the field of GPCR-targeted cancer therapy stands at the threshold of a paradigm shift. By embracing the multidimensional regulatory functions of these receptors within the TME, and by strategically deploying the full armamentarium of emerging technologies, it is possible to move beyond the intrinsic limitations of single-axis inhibition toward a new therapeutic paradigm. This paradigm would actively remodel the tumor ecosystem, anticipate and overcomes resistance mechanisms, and deliver more durable and curative outcomes for patients. The scientific foundation has been laid; the imperative now is to translate this understanding into clinical reality with the rigor that GPCR biology demands and the urgency that cancer patients deserve.

Cancer remains a formidable global health challenge, driving relentless innovation in therapeutic strategies. While targeted therapies and immune checkpoint blockers (ICBs) have markedly improved outcomes for select patient populations, the pervasive emergence of drug resistance and the intricate heterogeneity of the tumor microenvironment (TME) persist as major obstacles to achieving durable clinical remission [ 1 , 2 ]. Tumor cells can evade single-pathway inhibitors via mechanisms such as bypass activation, target mutation, or phenotypic switching; concurrently, the spatial heterogeneity of immunosuppressive cell infiltration, physical/metabolic barriers, and immune checkpoints within the TME contribute to limited response rates and heterogeneous efficacy observed with immunotherapies [ 3 , 4 ]. These challenges underscore the limitations inherent in single-pathway interventions, necessitating the exploration of novel molecular targets and multidimensional therapeutic paradigms capable of synergistically modulating both the intrinsic malignant properties of tumor cells and the dynamic equilibrium of the TME. Within this context, G protein-coupled receptors (GPCRs), as the largest family of human membrane proteins, have garnered widespread consensus as critical regulators of tumorigenesis and progression [ 5 , 6 ]. By orchestrating signaling cascades downstream of oncogenic drivers and mediating crosstalk within the TME, GPCRs influence virtually all hallmarks of cancer, including proliferation, metastasis, angiogenesis, and immune evasion [ 7 , 8 ]. For instance, the chemokine receptor CXCR4 drives tumor cell homing and distant metastasis via the CXCL12 axis; aberrant activation of metabotropic glutamate receptors (mGluRs) induces glioma proliferation and chemoresistance; LGR4 sustains pro-metastatic signaling by inhibiting epidermal growth factor receptor (EGFR) degradation through direct interaction; and GPRC5A promotes glycolysis and chemoresistance in pancreatic cancer by activating the Wnt/β-catenin pathway [ 9 – 12 ]. Their pivotal role is underscored by the fact that approximately 40% of FDA-approved drugs target these receptors, solidifying their status as one of the most productive classes of drug targets [ 13 ]. However, the very complexity that makes GPCRs attractive targets also presents a fundamental challenge that has been insufficiently addressed before. The function of a specific GPCR is not static but is exquisitely context-dependent, varying with cell type, spatial location, and temporal dynamics within the heterogeneous TME [ 14 ]. For instance, β2-adrenergic receptor signaling can promote tumor proliferation in cancer cells while simultaneously modulating the activity of anti-tumor immune cells [ 15 , 16 ]. Similarly, chemokine receptors like CXCR4 not only drive tumor cell metastasis but also recruit immunosuppressive cells, creating a complex, multi-compartmental signaling network [ 17 , 18 ]. This functional pleiotropy means that a traditional “one-size-fits-all” pharmacological approach—simply antagonizing or agonizing a single GPCR—may yield unpredictable or even opposing outcomes in different cellular compartments of the TME. This inherent limitation of conventional single-axis inhibition is a primary driver of the disappointing clinical translation and emerging resistance observed for many GPCR-targeted cancer therapies, a critical issue that remains underexplored in existing reviews. Therefore, rather than providing another broad overview of GPCR biology in cancer, this review focuses specifically on the “multidimensional regulatory conundrum” posed by GPCRs within the TME. We will first dissect how the same GPCR can exert divergent functions in cancer cells, immune cells, and stromal components, illustrating the complexity that confounds traditional targeting strategies. Subsequently, we will critically analyze the inherent limitations of current small molecules, peptides, and antibodies in navigating this complex landscape. Finally, we will spotlight a new wave of innovative therapeutic modalities—including allosteric and biased modulation, targeted protein degradation, nucleic acid therapeutics, and engineered cell therapies—that are uniquely poised to transcend single-axis inhibition and achieve the long-sought goal of orchestrated TME remodeling. By framing GPCRs not just as static targets but as dynamic nodes within a complex ecosystem, we aim to provide a transformative framework for the next generation of more effective and durable cancer therapies.

Understanding GPCRs’ multidimensional regulatory conundrum in the TME requires appreciating how their structural diversity and G protein-coupling drive context-dependent signaling. This complexity is compounded by aberrant subtype expression across tumor lineages. Therefore, delineating GPCR family features and target distribution across malignancies is not just cataloging but essential to reveal single-target limits and guide precise, context-aware interventions. GPCRs constitute the largest family of human membrane receptors, phylogenetically classified into five major families based on sequence homology and functional similarity: rhodopsin-like GPCRs (Class A), secretin GPCRs (Class B1), adhesion GPCRs (aGPCRs or Class B2), glutamate GPCRs (Class C), and frizzled GPCRs (Class F) (Fig. 1 ). Class A GPCRs represent the most extensively studied and largest subfamily, accounting for approximately 85% of all GPCR genes. These receptors feature a canonical 7-transmembrane domain (TMD) architecture, supplemented by an intracellular helix eight and a palmitoylated cysteine residue at the C-terminus. This class encompasses diverse subtypes, including aminergic, peptide, protein, lipid, melatonin, nucleotide, steroid, carbohydrate, sensory, and orphan receptors, mediating physiological processes ranging from sensory perception (visual/olfactory/gustatory) to cardiovascular regulation [ 19 ]. Class B GPCRs comprise two distinct subfamilies: secretin-like GPCRs (Class B1) and aGPCRs (Class B2) [ 20 , 21 ]. Class B1 members possess large extracellular domains (ECDs) that bind peptide hormone ligands such as parathyroid hormone (PTH), growth hormone-releasing hormone (GHRH), glucagon, and glucagon-like peptides (GLPs). The aGPCR family is characterized by unique N-terminal motifs, with most members containing a signature GPCR autoproteolysis-inducing (GAIN) domain within their ECDs. aGPCRs play critical roles in cellular adhesion and migration, significantly contributing to tumor cell invasion and metastasis [ 22 ]. Class C GPCRs are distinguished by a large ECD containing a cysteine-rich domain (CRD; except in GABAB receptors) and conserved venus fly trap (VFT) motifs at ligand-binding sites. Furthermore, these receptors typically exist as constitutively formed homo- or heterodimers mediated through N-terminal interactions, a configuration essential for receptor activation [ 23 ]. This class primarily includes mGluRs, γ-aminobutyric acid type B (GABA B ) receptors, calcium-sensing receptors (CaSRs), taste receptors (e.g., sweet/umami receptors TAS1Rs), and several orphan receptors. Class F GPCRs similarly feature an N-terminal CRD, connected to the TMD via a flexible intrinsically disordered linker, which serves as the primary binding site for endogenous ligands. This class encompasses 10 frizzled (FZD) receptors and the smoothened (SMO) receptor. SMO functions as the central transducer of the Hedgehog (Hh) signaling pathway, with small-molecule antagonists clinically approved as anticancer therapeutics [ 24 ]. FZD receptors mediate Wnt signaling pathways, governing critical functions in embryonic development and adult homeostasis, and are pathologically implicated in diverse diseases, including cancer, fibrotic disorders, and neurodegenerative conditions. Fig. 1 The structural features of distinct classes of GPCRs ( A ) and signal transduction pathway ( B ) The structural features of distinct classes of GPCRs ( A ) and signal transduction pathway ( B ) Despite significant divergences in ligand-recognition domains and activation mechanisms among the five major GPCR families, their core signaling universally involves conformational changes that activate heterotrimeric G proteins. This triggers dissociation of intracellular G proteins into Gα subunits and Gβγ dimers, subsequently regulating downstream effectors [ 25 ]. Among these, the Gα subunit-mediated signaling represents the canonical pathway. Distinct Gα subunits (Gs, Gi/o, Gq/11, and G12/13) activate specific effector enzymes to generate second messengers or modulate ion channels. Notably, substantial differences exist in G protein-coupling preferences across GPCR families, intimately correlated with their intrinsic structural features and ligand-binding properties [ 26 , 27 ]. For instance, the vast majority of Class A GPCRs predominantly couple to Gq/11, Gi/o, or Gs, with selectivity governed by specific structural features within transmembrane domains and ligand-binding pockets. Class F GPCRs exhibit more diversified signaling modalities. FZD receptors primarily signal independently of G proteins in the canonical Wnt pathway via Dishevelled (Dvl) proteins, whereas in non-canonical Wnt pathways (e.g., Wnt/Ca 2 + signaling), they activate Gq/11 and G12/13 [ 28 ]. SMO principally couples to Gi upon ligand binding, transducing Hh signals through adenylate cyclase (AC) inhibition and concomitant activation of PI3K/AKT and RhoA pathways [ 29 ]. Beyond the canonical G protein-dependent pathways, GPCRs also signal through β-arrestin-dependent non-canonical mechanisms [ 30 ]. β-arrestin mediates receptor desensitization and internalization to terminate signaling, while also functioning as a scaffold protein to initiate alternative pathways such as MAPK cascades, thereby expanding the complexity and diversity of GPCR signaling networks [ 31 ]. Research by Qu et al. elucidated the scaffolding mechanism of β-arrestin 2 in the cRaf/MEK1/ERK cascade, demonstrating that β-arrestin 2 interacts with cRaf, MEK1, and ERK2 through distinct domains. Crucially, β-arrestin 2 binding to cRaf occurs independently of its activation state, whereas engagement with MEK1 and ERK2 requires its activated conformation [ 32 ]. This mechanism facilitates ERK1/2 activation by orchestrating the spatial organization of signaling components, offering novel perspectives for targeting GPCR pathways. This rich diversity in signaling mechanisms and coupling preferences provides the molecular basis for the context-dependent functions of GPCRs in cancer, setting the stage for examining how specific receptor subtypes are aberrantly expressed across different tumor types and contribute to malignant progression. Aberrant expression or mutations of GPCRs significantly impact tumor development and therapeutic responses by dysregulating intrinsic growth/survival signaling in cancer cells and disrupting TME crosstalk [ 33 ]. The distribution of these receptors as oncological targets exhibits remarkable pervasiveness and complexity, with dysregulated expression spanning virtually all major cancer types and involving diverse receptor subtypes. Crucially, expression patterns of distinct GPCR subtypes correlate closely with tumor stage, molecular subtypes, TME composition, and treatment status, directly influencing patient prognosis and therapeutic decision-making. Given the pivotal roles of GPCRs in tumor progression, targeting these receptors has emerged as a highly promising antineoplastic approach. This section delineates GPCR subtypes with established oncological relevance, their distribution characteristics, and therapeutic implications. In the following sections, we delineate the major GPCR subtypes with established oncological relevance, highlighting how their structural and signaling features translate into distinct pro-tumorigenic functions and, critically, how their pleiotropic roles within the TME contribute to the multidimensional regulatory conundrum introduced earlier. Chemokine receptors, belonging to Class A GPCRs, are predominantly expressed on immune cells and vascular endothelia. They modulate pathological processes including immune cell migration, tumor angiogenesis, and metastasis through Gαi protein- or β-arrestin-dependent signaling [ 34 ]. Clinical evidence confirms that aberrant activation of chemokine receptors serves as a key driver in remodeling immunosuppressive TMEs. For instance, hyperactivation of the CXCL12–CXCR4 axis in diverse solid tumors, such as lung and breast carcinomas, recruits substantial immunosuppressive regulatory T cells (Tregs), MDSCs, significantly compromising treatment response rates [ 35 , 36 ]. Chemokine receptors comprise 19 members interacting with 48 ligands, classified into four major subtypes based on ligand characteristics: XCR, CCR, CXCR, and CX3CR. CXCR subtypes demonstrate the most extensive tumor-associated expression profiles and are mechanistically well-characterized. CXCR4 represents a prototypic oncology target, overexpressed in at least 23 cancer types, including breast and ovarian carcinomas, with significant correlation to poor patient prognosis [ 37 ]. Ligand engagement by CXCL12 (SDF-1) activates downstream PI3K/AKT and MAPK signaling cascades, driving tumor cell proliferation, neovascularization, invasive metastasis, and chemoresistance development [ 38 , 39 ]. CXCR1/2 signaling upon CXCL8 (IL-8) binding recruits tumor-associated neutrophils (TANs) and tumor-associated macrophages (TAMs), promoting cancer stem cell proliferation and conferring therapy resistance [ 40 ]. The CXCR2 inhibitor reparixin demonstrated synergistic enhancement with chemotherapy or immunotherapy by impeding immunosuppressive cell recruitment and angiogenesis [ 41 ]. Additionally, CXCR5 specifically mediates B-cell trafficking in lymphomas, while aberrant CXCR7 expression in tumor vasculature implicates its potential therapeutic relevance [ 42 , 43 ]. CCR subtypes similarly demonstrate critical involvement in tumor progression. For instance, CCL5-activated CCR5 signaling promotes immunosuppressive microenvironment formation via PI3K/AKT and NF-κB pathways; the CCR4–CCL17 axis drives Tregs infiltration into tumor tissues, while the CCR7–CCL21 axis mediates lymph node metastasis in lymphomas [ 44 – 46 ]. Therapeutic strategies targeting chemokine receptors are becoming increasingly diversified. Beyond small-molecule antagonists (e.g., CXCR4-targeted plerixafor), monoclonal antibodies (e.g., anti-CCR5 leronlimab), bispecific antibodies, and combination therapies (e.g., CXCR4 antagonists plus PD-1 inhibitors) are advancing through clinical translation [ 47 , 48 ]. However, the dual role of chemokine receptors, promoting both tumor dissemination and immunosuppressive recruitment, exemplifies the functional pleiotropy complicating therapeutic targeting. A single antagonist might inhibit metastasis and relieve immunosuppression but could also disrupt beneficial immune trafficking, underscoring the need for context-specific modulation. Gonadotropin-releasing hormone (GnRH), also known as luteinizing hormone-releasing hormone (LHRH), is a decapeptide neurohormone secreted by the hypothalamus, existing as two isoforms: GnRH-I and GnRH-II. Its receptor, GnRHR, belongs to Class A GPCRs, with widespread distribution in pituitary gonadotrophs and extragonadal tissues, including lymphocytes, breast, ovaries, and prostate [ 49 ]. Upon GnRH binding, GnRHR primarily activates phosphatidylinositol-calcium signaling, stimulating pituitary secretion of luteinizing hormone (LH) and follicle-stimulating hormone (FSH), thereby regulating gonadal steroidogenesis (e.g., testosterone, estrogen) and reproductive functions. Notably, GnRHR overexpression is prevalent in hormone-dependent malignancies such as breast, prostate, ovarian, and endometrial carcinomas [ 50 , 51 ]. GnRHR signaling drives tumor growth and metastatic progression through direct and indirect stimulation of steroidogenesis. For instance, testicular testosterone secretion critically stimulates prostate cancer cell proliferation, whereas ovarian-derived estrogens and progesterone are mechanistically linked to uterine fibroid pathogenesis and endometriosis progression. Consequently, suppressing relevant hormone levels constitutes a cornerstone therapeutic strategy for these conditions. Initial GnRHR-targeting strategies predominantly employed peptide agonists exemplified by leuprorelin. These agents induce receptor desensitization and internalization through sustained activation, consequently suppressing LH/FSH secretion and reducing gonadal steroids to castration levels (termed “chemical castration”). This therapeutic approach is extensively applied in prostate cancer (androgen deprivation therapy), premenopausal breast cancer, and endometriosis management [ 52 ]. However, GnRH agonists frequently elicit an initial “flare phenomenon”, characterized by transient surges in gonadal hormones that hyper-stimulate receptors and may temporarily exacerbate symptoms. To circumvent this limitation, subsequent development prioritized GnRH antagonists (e.g., degarelix) that directly block receptor activity [ 53 ]. By competitively inhibiting GnRHR, antagonists prevent initial hormonal surges, enabling rapid and sustained reduction of sex hormones to castration levels. This pharmacodynamic profile renders them particularly valuable for advanced prostate cancer patients requiring avoidance of hormonal fluctuations, or as conservative management for early-stage endometrial carcinoma patients preserving fertility potential. The GnRHR case reveals another layer of complexity: even the same receptor can produce dramatically different clinical outcomes depending on whether an agonist or antagonist is employed, underscoring the importance of understanding receptor dynamics in therapeutic design. Somatostatin receptors (SSTRs), prototypical GPCRs, transduce somatostatin signaling to regulate key physiological processes, including metabolism, somatic growth, and hormonal secretion. SSTR dysfunction is mechanistically linked to endocrine disorders (e.g., acromegaly), neurological pathologies, and diverse malignancies [ 54 ]. The five human SSTR subtypes (SSTR1-5) exhibit subtype-specific distribution. Overexpression of SSTR2 and SSTR5 in neuroendocrine tumors (NETs) and pituitary adenomas establishes them as primary clinical targets [ 55 ]. Furthermore, prevalent SSTR expression in meningiomas, breast carcinomas, colorectal cancers, and other solid tumors underscores their pan-cancer therapeutic relevance [ 56 ]. Somatostatin binding inhibits growth hormone (GH) secretion, modulates hypothalamic-pituitary axis activity, and regulates gastrointestinal/pancreatic functions, consequently suppressing cellular proliferation and angiogenesis. In oncological contexts, SSTR hyperactivation or dysregulated expression drives malignant progression by facilitating immune evasion, metabolic reprogramming, and therapy resistance. Notably, SSTR2-specific overexpression in pancreatic NETs serves as a theranostic biomarker for tumor imaging and targeted interventions [ 57 ]. Within targeted anticancer therapies, SSTRs represent one of the most extensively and successfully translated GPCR families. The primary therapeutic strategy involves designing somatostatin analogs (SSAs) that activate SSTRs to suppress hormonal hypersecretion and induce tumor cell cycle arrest. SSAs exemplified by octreotide have become first-line therapeutics for neuroendocrine neoplasms (NENs). Next-generation approaches employ peptide receptor radionuclide therapy (PRRT), utilizing radiolabeled SSAs (e.g., 177 Lu- or 90 Y-conjugated analogs) to selectively target SSTRs on tumor cells [ 58 ]. This modality achieves precise intracellular radionuclide delivery via receptor-mediated endocytosis, eradicating tumor cells through β-particle emission while significantly prolonging progression-free survival (PFS) in advanced NET patients. Given functional heterogeneity among SSTR subtypes (e.g., SSTR3-mediated apoptosis potentially damaging normal tissues), developing subtype-selective agonists constitutes a critical approach to minimize off-target toxicity. Furthermore, chronic SSA administration may induce receptor desensitization or compensatory activation of downstream pathways (e.g., mTOR signaling), necessitating rational combinations with targeted inhibitors (e.g., everolimus) to overcome resistance [ 59 ]. Despite the clinical success of SSTR-targeted analogs, adaptive resistance inevitably emerges through pathway crosstalk (e.g., mTOR activation), underscoring the necessity of combination strategies designed to engage the broader signaling network. aGPCRs constitute the second-largest GPCR subclass with highly conserved evolutionary features. They exhibit broad expression across mammalian organ systems, modulating critical physiological processes including cell adhesion, migration, paracrine signaling, and tissue morphogenesis [ 60 , 61 ]. The human genome encodes 33 aGPCR members, most of which remain orphan receptors. Emerging as promising therapeutic targets due to their roles in oncological, reproductive, and neurological disorders, aGPCRs, particularly the extensively studied GPR56 (ADGRG1), have garnered significant drug development interest [ 62 ]. Studies revealed GPR56 overexpression in breast cancer cells relative to normal tissues, where it drives cancer cell proliferation, migration, and invasion through multiple signaling axes. Genetic silencing of GPR56 potently suppressed these malignant phenotypes, underscoring its therapeutic potential [ 63 ]. Furthermore, aberrant GPR56 expression in colorectal cancer, melanoma, acute myeloid leukemia (AML), and acute lymphoblastic leukemia (ALL) positions it as a diagnostic/prognostic biomarker and viable therapeutic target. Pharmacological targeting of its GAIN domain or downstream effectors (e.g., RhoA/E-cadherin pathways) may yield novel strategies to inhibit metastasis and overcome drug resistance. For instance, the resveratrol analog DMU-214, a putative GPR56 inhibitor, revealed enhanced antitumor efficacy over its parent compound DMU-212 [ 64 ]. Research indicated that ELTD1 (ADGRL4), an orphan aGPCR member upregulated in glioma-associated vasculature, its deficiency would normalize tumor vasculature, reducing vascular leakage and hypoxia while enhancing T-cell infiltration post-PD-1 blockade [ 65 ]. This exemplifies how GPCR targeting can not only directly suppress tumor proliferation but also enhance therapeutic efficacy by vascular normalization and potentiated immune cell recruitment. Notwithstanding the established pro-tumorigenic mechanisms and therapeutic potential of aGPCRs across diverse solid and hematological malignancies, their drug development confronts substantial hurdles. aGPCRs exhibit intricate conformational dynamics within their 7TMDs coupled with extraordinary diversity in natural ligands; critically, approximately half remain orphan receptors with endogenous ligands uncharacterized, obscuring the molecular basis for targeted modulation. These collective factors compound the challenges in rational drug design, thereby limiting most current targeting strategies to preclinical investigation. SMO, a Class F GPCR, serves as the central transducer of the Hh signaling pathway. It critically regulates embryonic development and adult stem cell maintenance, while its aberrant activation drives oncogenesis through Hh pathway dysregulation [ 66 ]. In the absence of Hh ligands, the transmembrane protein Patched (Ptch) inhibits SMO, sequestering the downstream transcription factor Gli in the cytoplasm and repressing pro-oncogenic gene expression; upon ligand binding, SMO is released, facilitating Gli nuclear translocation to initiate transcription of pro-proliferative and pro-angiogenic genes. Hh pathway dysregulation is implicated in multiple malignancies. Mutations in Hh components, documented in both familial and sporadic cases, are hallmark features of basal cell carcinoma and medulloblastoma [ 67 ]. Recent studies further identifed aberrant Hh activation in aggressive solid tumors including small cell lung cancer and pancreatic adenocarcinoma, providing molecular rationale for targeted intervention [ 68 ]. SMO-targeted drug development primarily focuses on small-molecule antagonists. SMO inhibitors such as vismodegib, sonidegib, which block Gli activation, are clinically approved for basal cell carcinoma management. To address clinical resistance mechanisms (e.g., SMO mutations, Gli-independent pathway activation), novel allosteric inhibitors and combination strategies (e.g., SMO inhibitors plus immune ICBs) are advancing through clinical development, offering new avenues to expand therapeutic indications to solid tumors [ 69 ]. SMO inhibitors represent a rare success story among GPCR-targeted cancer drugs, yet resistance inevitably emerges via mutations and pathway reactivation, underscoring the need for strategies that can outpace tumor adaptation. FZD receptors represent atypical GPCRs that form the core of Class F family, with their extracellular N-terminal CRDs specifically binding endogenous ligands encompassing 19 Wnt proteins and Norrin. Wnt ligands engage distinct FZD subtypes to activate canonical (Wnt/β-catenin) or non-canonical pathways, whereas Norrin exclusively binds FZD4 to regulate blood-retinal barrier functions [ 70 ]. By orchestrating Wnt signaling, FZD receptors play pivotal roles in tumorigenesis, metastasis, and cancer stem cell (CSC) maintenance. Studies revealed Wnt/β-catenin pathway dysregulation in approximately 30% of solid tumors (e.g., colorectal, hepatic, and breast carcinomas), characterized by aberrant nuclear accumulation of β-catenin and consequent oncogene overexpression (e.g., c-Myc, CyclinD1) [ 71 ]. For instance, FZD5 overexpression in pancreatic cancer facilitated cholesterol binding that promoted receptor palmitoylation and membrane trafficking, amplifying Wnt-driven tumor proliferation [ 72 ]. Furthermore, canonical Wnt activation expands CSC populations, remodels immunosuppressive microenvironments, and confers therapy resistance [ 73 ]. Researchers resolved the unliganded three-dimensional (3D) structure of human FZD4, uncovering unique ligand-binding pocket topology distinct from classical GPCRs, providing critical structural insights for designing novel FZD-targeted agents (Fig. 2 ) [ 74 ]. Current therapeutic strategies primarily focus on disrupting Wnt ligand-receptor binding to inhibit downstream pathway activation. Although no FZD-targeting drugs have reached clinical approval, preclinical studies demonstrated promising outcomes that establish foundations for future development. FZD receptors highlight how atypical signaling (e.g., G protein-independent pathways) and complex ligand-receptor interactions create unique targeting challenges, while offering opportunities for novel modalities such as antibody-based inhibitors that block specific Wnt-FZD interactions. Fig. 2 The arrangement of the extracellular side of FZD4 and other GPCRs. In FZD4 ( A ) and SMO ( B ), ECL2 acts as a plug and the individual fragments of the extracellular region (hinge domain, ECLs) form a compact structure. In GCGR ( C ), GLP-1 R ( D ) and mGlu-1 R ( E ), the organization of the extracellular region is less compact so either an antibody or a ligand is required for stabilization of the 7TM and/or the ECD. ECDs for SMO, GCGR and GLP-1 R are derived from full-length structures, and for mGlu-1 R a partial model (PDB: 2E4W) is presented. Adopted from Ref. [ 74 ] The arrangement of the extracellular side of FZD4 and other GPCRs. In FZD4 ( A ) and SMO ( B ), ECL2 acts as a plug and the individual fragments of the extracellular region (hinge domain, ECLs) form a compact structure. In GCGR ( C ), GLP-1 R ( D ) and mGlu-1 R ( E ), the organization of the extracellular region is less compact so either an antibody or a ligand is required for stabilization of the 7TM and/or the ECD. ECDs for SMO, GCGR and GLP-1 R are derived from full-length structures, and for mGlu-1 R a partial model (PDB: 2E4W) is presented. Adopted from Ref. [ 74 ] Beyond the aforementioned core subtypes, several additional receptor families, including metabolism/energy-regulating receptors, lipid-sensing receptors, neurotransmitter/hormone receptors, and orphan receptors, demonstrate unique antitumor potential by modulating tumor metabolism, immune microenvironments, and transmembrane signaling transduction [ 75 ]. These receptors exert synergistic or compensatory roles mechanistically interconnected with previously discussed chemokine and adhesion receptors, collectively broadening the scope of GPCR-targeted therapeutic strategies. Growth hormone secretagogue receptor (GHSR), a master regulator of energy metabolism, transduces ghrelin signaling to stimulate GH release and modulate glucose/lipid homeostasis. Aberrant ghrelin/GHSR expression across malignancies, combined with significant efficacy of GHSR agonists in cancer cachexia, establishes this axis as a prime target for nutritional-metabolic intervention in oncology [ 76 ]. Glucagon receptor (GCGR) similarly orchestrates tumor cell metabolic reprogramming and immune microenvironment remodeling, providing innovative frameworks for metabolically targeted therapies [ 77 ]. Lipid-sensing GPCRs are increasingly implicated in tumor pathogenesis. The sphingolipid metabolite sphingosine-1-phosphate (S1P) modulates tumor growth, metastasis, and immune evasion by engaging S1PR1-5 receptors. For instance, S1PR1 overexpression in hepatocellular carcinoma promotes tumor angiogenesis through downregulation of CerS3 [ 78 ], while S1PR2 fosters immunosuppressive microenvironments by impeding immune cell infiltration [ 79 ]. Selective targeting of S1PR1-5 signaling effectively inhibits S1P-mediated cancer growth, proliferation, and dissemination [ 80 ]. Lysophosphatidic acid receptors (LPAR1-6), another lipid-related GPCR subclass, similarly promote tumor cell proliferation, invasion, and metastasis through diverse signaling cascades, establishing their significance as antitumor targets. Mechanistic studies revealed that LPA-LPAR signaling stimulates urothelial carcinoma-associated 1 (UCA1) expression, which subsequently sequesters let-7 miRNAs to derepress oncogenes Ras and c-Myc, thereby driving ovarian cancer progression. siRNA-mediated UCA1 silencing suppresses tumor growth in ovarian cancer xenograft models, revealing a novel therapeutic strategy [ 81 ]. Furthermore, the LPAR inhibitor Ki16425 impeded T-cell lymphoma progression by inducing apoptosis, suppressing glycolysis, and activating antitumor immune responses [ 82 ]. Multiple neurotransmitter and stress-related receptors, including adrenergic, dopamine, histamine, serotonin (5-HT), prolactin, and angiotensin receptors, modulate cancer progression via neuro-tumor crosstalk. Retrospective clinical analysis revealed that angiotensin receptor blockers improved survival in early-stage lung cancer patients receiving stereotactic body radiotherapy [ 83 ]. Overexpressed in gliomas, dopamine receptor D2 (DRD2) is targeted by antagonists like ONC201 that induced tumor cell apoptosis via activation of the integrated stress response, with this agent advancing to Phase II clinical trials [ 84 ]. The serotonin receptor HTR2B promoted tumor growth through ERK signaling, with its selective antagonist SB204741 exhibiting anti-proliferative activity in colorectal cancer models [ 85 ]. Beyond these receptors, gastrin-releasing peptide receptor (GRPr) emerges as a promising GPCR target. In the COMBAT trial, GRPr-targeted theranostic agents [ 64 ]Cu-SAR-BBN and [ 67 ]Cu-SAR-BBN demonstrated therapeutic potential for metastatic castration-resistant prostate cancer patients, particularly those with low/no prostate-specific membrane antigen expression [ 86 ]. In addition, over 100 orphan receptors within the GPCR superfamily remain functionally uncharacterized, yet their aberrant expression in tumors implies potential therapeutic relevance. Exemplary candidates include: GPR35 investigated for allergic inflammation therapy, leucine-rich repeat-containing GPR48 (LGR4) and LGR5 targeted for gastrointestinal disorders, and GPR55 explored as an antispasmodic target [ 87 – 89 ]. Notably, the orphan receptor GPRC5D demonstrates specific expression in multiple myeloma (MM), where the antibody-drug conjugate (ADC) talquetamab directed against this receptor has demonstrated groundbreaking efficacy, offering valuable insights for solid tumor therapeutics [ 90 ]. In summary, as pivotal anticancer targets, GPCRs exhibit remarkable diversity and regulatory complexity. These receptors broadly participate in tumor progression through direct tumor proliferation and invasion driving or indirect immunosuppressive microenvironments remodeling and metabolic reprogramming. Current research has identified approximately 160 GPCR proteins implicated in tumorigenesis, predominantly within Class A (Fig. 3 ). Among these, roughly 70 targets have corresponding agents in preclinical development, clinical trials, or approved clinical use (though not all indications are oncology-related). The remaining 90 targets, however, remain validated yet undrugged. Notably, a substantial fraction of this latter group comprises orphan receptors, whose undefined endogenous ligands obscure mechanistic clarity and further impede therapeutic development. This stark disparity—90 target opportunities awaiting intervention—underscores the pressing need for innovative strategies capable of embracing GPCR complexity beyond conventional targeting paradigms. Fig. 3 Neoplasm-associated GPCR proteins. Clinical-tapped targets comprise those with approved drugs and those with investigational agents currently undergoing clinical trials. Approved drugs referenced herein encompass, but are not limited to, oncology indications. Data were manually collected, cleaned and curated from Open Targets, DrugBank and ClinicalTrials.gov. This visualization was created with the GPCRdb Data Mapper (accessible at https://gpcrdb.org/mapper/ ) Neoplasm-associated GPCR proteins. Clinical-tapped targets comprise those with approved drugs and those with investigational agents currently undergoing clinical trials. Approved drugs referenced herein encompass, but are not limited to, oncology indications. Data were manually collected, cleaned and curated from Open Targets, DrugBank and ClinicalTrials.gov. This visualization was created with the GPCRdb Data Mapper (accessible at https://gpcrdb.org/mapper/ )

The preceding sections have established that GPCRs function as dynamic, context-dependent regulators within the TME, a complexity that conventional targeting approaches struggle to address. Yet, this very complexity also opens new avenues for therapeutic intervention. Therapeutic strategies targeting GPCRs for anticancer applications encompass diverse approaches, with conventional modalities primarily comprising small-molecule compounds, peptides, and antibodies. Continuous advancements in biotechnology have catalyzed the emergence of novel paradigms, including targeted protein degradation, gene silencing, and cellular therapies. Small-molecule drugs dominate GPCR-targeted therapies due to their high oral bioavailability, superior membrane permeability, and established synthetic scalability. Capitalizing on the inherent small-molecule nature of most native GPCR ligands, developing orthosteric site-targeted agonists/antagonists represents a classical approach. These compounds competitively or non-competitively bind hydrophobic pockets within the TMD, modulating activation status of G protein or β-arrestin signaling pathways to inhibit tumor proliferation/migration and induce apoptosis. Clinically successful representatives include SMO antagonists and chemokine receptor antagonists. As paradigm-targeting agents for Hh signaling, three small-molecule SMO antagonists have gained global approval for tumors driven by aberrant Hh pathway activation. Vismodegib (FDA-approved 2012), the inaugural Hh pathway inhibitor, achieved objective response rates (ORR) of 30%-43% in advanced basal cell carcinoma with a median duration of response of 7.6 months [ 91 ]. Sonidegib (NVP-LDE225), originating from Novartis research following high-throughput screening and structure-activity relationship optimization, was approved in 2015 for adult basal cell carcinoma as the second SMO antagonist [ 92 ]. Glasdegib maleate from Pfizer constitutes the third approved SMO antagonist, securing orphan drug designation in the US and EU as the first SMO-targeted agent for adult AML, with subsequent multi-country approvals enabling investigation across expanded indications [ 93 , 94 ]. Plerixafor, the first approved small-molecule CXCR4 inhibitor, demonstrated unique value in hematological malignancies. By blocking tumor cell homing to bone marrow niches, it significantly boosts hematopoietic stem cell mobilization efficiency in MM and AML patients (achieving > 90% CD34+ cell collection success) and synergistically enhances chemo/radiotherapy responses. Moreover, certain approved drugs exhibit latent anticancer activities, driving growing interest in their “drug repurposing” potential. For instance, antihistamines have been shown to potentiate immunotherapy responses in cancer patients by modulating immune microenvironments [ 95 ]. Additionally, combined administration of the β2-AR antagonist propranolol and bevacizumab significantly reduced tumor burden in colorectal cancer (CRC) xenograft models, a phenomenon linked to reversal of β2-AR overexpression-associated chemoresistance and extension of PFS [ 96 ]. Furthermore, natural products harbor abundant GPCR-targeting lead compounds warranting systematic exploration (Fig. 4 ) [ 97 ]. Fig. 4 Diversity of GPCR ligands derived from traditional medicines. The representative ligands listed in the middle circle exhibit diverse chemical structures, encompassing alkaloids, flavonoids, organic acids, and terpenoids. These compounds sourced from a variety of herbs that are shown in the outermost circle, such as Ginkgo biloba, Sideritis montana, and Pausinystalia johimbe. Adopted from Ref. [ 97 ] Diversity of GPCR ligands derived from traditional medicines. The representative ligands listed in the middle circle exhibit diverse chemical structures, encompassing alkaloids, flavonoids, organic acids, and terpenoids. These compounds sourced from a variety of herbs that are shown in the outermost circle, such as Ginkgo biloba, Sideritis montana, and Pausinystalia johimbe. Adopted from Ref. [ 97 ] Despite these successes, small-molecule agents often encounter significant clinical hurdles, as their pleiotropic effects not only risk on-target off-tumor toxicity but also face selectivity limitations imposed by the evolutionary conservation of orthosteric pockets across receptor subtypes. Moreover, as seen with SMO inhibitors, resistance inevitably emerges through mutations or pathway reactivation, a direct consequence of targeting a single node in a highly adaptive signaling network. Peptide and peptidomimetic therapeutics demonstrate significant potential in GPCR-targeted interventions by emulating or structurally optimizing native ligands for high-affinity and subtype-selective binding. However, endogenous peptides exhibit susceptibility to proteolytic degradation and short plasma half-lives (e.g., somatostatin: merely 2–3 minutes). To address this, researchers employ strategies including D-amino acid substitution for L-isomers, backbone cyclization, and protective group addition to enhance metabolic stability and prolong in vivo pharmacokinetics [ 98 ]. Clinically implemented representatives encompass SSAs and GnRH analogs. Exemplified by octreotide (approved 1988), core pharmacophore preservation (Phe-D-Trp-Lys-Thr) combined with structural modifications (N-terminal D-Phe, C-terminal Thr-ol extension) enhanced GH suppression potency 3-fold and significantly prolonged half-life. As the first long-acting cyclic octapeptide, octreotide activates SSTR2/SSTR5 to inhibit hormonal secretion in NETs but requires daily subcutaneous administration (1–3 injections). Lanreotide, a synthetic octapeptide derivative with structural/functional similarity to octreotide, exhibits extended half-life; its sustained-release microsphere formulation enables once-monthly dosing [ 99 ]. The pan-SSTR agonist pasireotide (approved 2012, targeting SSTR1/2/3/5) remains effective in octreotide-resistant patients, though clinical utility is limited by hyperglycemia induction [ 100 ]. Additionally, peptide receptor radionuclide agents like 177 Lu-Lutathera® are approved for SSTR-positive adult patients with gastroenteropancreatic (GEP) NETs. The GnRH analog leuprolide (developed by Takeda) induces pituitary desensitization via sustained GnRHR agonism, achieving “chemical castration” by reducing testosterone to castrate levels (<50 ng/dL) in advanced prostate cancer [ 101 ]. Other marketed GnRHR agonists include goserelin from AstraZeneca, buserelin from Sanofi, nafarelin from Pfizer, and gonadorelin from Mitsubishi Tanabe Pharma. Notably, peptide-drug conjugate (PDC) represents an emerging strategy. Conventional docetaxel (DTX) for breast cancer upregulates CXCR4, increasing metastasis risk. The nanoparticulate conjugate linking CXCR4-antagonistic peptide CTCE with DTX demonstrated potent suppression of bone-specific and pulmonary metastases in triple-negative breast cancer through dual blockade of metastatic pathways and cytotoxic effects [ 102 ]. While peptide/peptidomimetic agents exploit receptor-ligand binding specificity to enhance targeting precision, their clinical translation is often tempered by inherent pharmacological limitations. Metabolic instability frequently necessitates chemical modifications or specialized delivery systems to improve bioavailability and brain penetration [ 103 ]. Moreover, their relatively large molecular size can impede tumor tissue penetration, further constraining therapeutic efficacy. Even highly specific agonists, exemplified by pasireotide, may elicit unintended metabolic side effects due to broad target expression in normal tissues, underscoring the persistent challenge of GPCR pleiotropy in drug development. Despite the dominance of small molecules in GPCR-targeted therapies, inherent limitations including off-target toxicity, drug resistance, and metabolic instability, have propelled antibody-based agents as emerging strategies to overcome these bottlenecks [ 104 , 105 ]. Compared to small molecules, antibodies targeting ECDs (e.g., CCR4 N-terminus) or allosteric sites (e.g., GPRC5D CRD region) circumvent cross-reactivity from TMD conservation, significantly enhancing targeting specificity. This advantage drives development of monoclonal antibodies (mAbs), bispecific antibodies (BsAbs), ADCs, and nanobodies [ 106 ]. mAbs directly eliminate malignant cells via Fc-mediated antibody-dependent cellular cytotoxicity (ADCC), while BsAbs concurrently engage GPCRs and immune checkpoint receptors or tumor antigens to potentiate immune cell recognition and tumor killing. ADCs comprising cytotoxic payloads conjugated to mAbs via chemical linkers, exploit high GPCR internalization rates for precise toxin delivery, minimizing off-tissue effects and improving therapeutic indices. Emerging nanobodies, naturally lacking light chains, offer advantages of low molecular weight, enhanced stability, and facile engineering for improved solid tumor penetration [ 107 ]. For instance, the APJ-targeting nanobody JN241 inserts its CDR3 loop into the orthosteric pocket, with its crystal structure enabling rational conversion from antagonist to agonist [ 108 ]. Nanobody-assisted structural determination has resolved > 340 GPCR conformations, exemplified by the β2-AR/Nb80 complex revealing G protein-mimetic binding mechanisms [ 109 ]. The epitope-guided anti-CXCR2 antibody developed by Shi et al. blocks IL-8-induced neutrophil chemotaxis by binding the N-terminal domain, significantly ameliorating experimental autoimmune encephalomyelitis in murine models [ 110 ]. Jacob et al. demonstrated that the GPR56-targeted ADC (10C7 mAb conjugated to duocarmycin) selectively kills CRC cells at low-nanomolar concentrations and suppresses tumor growth in xenografts, offering novel therapeutic avenues for ~80–85% of microsatellite-stable CRC patients [ 111 ]. Among the four GPCR-targeting antibody drugs currently approved globally, two represent milestone innovations in the treatment of hematological malignancies. Mogamulizumab, the world’s first GPCR antibody drug, is primarily indicated for adult T-cell leukemia/lymphoma and cutaneous T-cell lymphoma (CTCL). Mogamulizumab specifically binds to the N-terminal domain of CCR4, featuring a defucosylated design that enhances its ADCC effect. The Phase III MAVORIC study demonstrated that mogamulizumab significantly prolonged PFS compared to the small molecule drug vorinostat in patients with CTCL (7.7 months vs. 3.1 months), with a hazard ratio of 0.53 [ 112 ]. Talquetamab is the world’s first bispecific antibody, simultaneously targeting GPRC5D (a novel target on MM cells) and CD3 (a receptor on cancer-fighting T cells). In the Phase II MonumenTAL-1 study, patients with relapsed or refractory multiple myeloma (RRMM) receiving a 0.4 mg/kg subcutaneous dose achieved an ORR of 74%, with a ≥very good partial response rate of 59% and a median PFS of 7.5 months, establishing a novel paradigm for GPCR-immunotherapy synergy [ 113 ]. Presently, numerous antibody-based therapeutics targeting GPCRs are under development, including an anti-CXCR4 ADC conjugated to auristatin, a bispecific nanobody simultaneously targeting CXCR4 and PD-L1 [ 114 , 115 ]. The investigational CCR8-targeting antibody LM-108, combined with an anti-PD-L1 antibody, has demonstrated promising clinical activity in gastric and pancreatic cancers. [ 116 , 117 ] A Phase II, single-arm, multicenter, open-label clinical trial evaluating this combination in patients with advanced malignant solid tumors is currently being conducted. The clinical success of mogamulizumab and talquetamab exemplifies the potential of antibody-based strategies in engaging immune effector mechanisms. Yet, their efficacy has largely remained confined to hematological malignancies. In solid tumors, however, the physical and immunosuppressive barriers of the TME continue to impede antibody penetration and function, underscoring the need for strategies aimed at actively remodeling the tumor ecosystem rather than merely engaging it. Table 1 summarizes currently approved GPCR-targeting antineoplastic drugs, which predominantly engage Class A family members such as SSTR, GnRH, chemokine, and smoothened receptors. While successful, these agents address only a fraction of the GPCR superfamily, leaving numerous receptors with critical roles in cancer, like aGPCRs and orphan receptors, entirely undrugged, underscoring a key therapeutic gap. This disparity underscores that the conventional ligand-receptor occupancy paradigm, though effective for certain targets, is insufficient to capture the full regulatory complexity of GPCRs in oncology. It is precisely this limitation that calls for next-generation therapeutic strategies. Table 1 Listed GPCR-targeted antineoplastic drugs Class Receptors Drugs Drug type Modality Indication First approval A CXCR4 Plerixafor SM Antagonist Non-Hodgkin’s lymphoma or MM 2008 A CCR4 Mogamulizumab mAb Antagonist T-cell lymphoma 2018 A CXCR4 Motixafortide Peptide Antagonist MM 2023 A SSTR1/2/5 Octreotide Peptide Agonist Carcinoidd tumor 1988 A SSTR1/2/3/5 Pasireotide Peptide Agonist NETs A SSTR Pentetreotide Peptide Antagonist Carcinoid tumors, GEP-NETs 1994 A SSTR2/5 Lanreotide Peptide Agonist GEP-NETs 2007 A SSTR2 Dotatate gallium Ga-68 PRC Antagonist NETs 2016 A SSTR2 Lutetium Lu 177 dotatate PRC Agonist GEP-NETs 2018 A SSTR2 Copper oxodotreotide Cu-64 PRC Agonist NETs 2020 A GnRHR Gonadorelin Peptide Agonist Breast cancer, prostate cancer 1982 A GnRHR Buserelin Peptide Agonist Breast cancer, prostate cancer 1985 A GnRHR, LSHR Goserelin Peptide Agonist Breast cancer, prostate cancer 1989 A GnRHR Nafarelin Peptide Agonist Breast cancer 1990 A GnRHR1 Cetrorelix Peptide Antagonist Prostate, uterine fibroids 2000 A GnRHR1 Triptorelin Pamoate Peptide Agonist Prostate cancer, uterine fibroids 2000 A GnRHR1 Abarelix Peptide Antagonist Prostate cancer 2003 A GnRHR Histrelin Peptide Agonist Prostate cancer 2004 A GnRHR Degarelix Peptide Antagonist Prostate cancer 2008 A GnRHR Relugolix SM Antagonist Uterine fibroids, prostate cancer 2019 A GnRHR Leuprolide mesylate Peptide Agonist Prostate cancer 2021 A GnRH Linzagolix SM Antagonist Uterine fibroids 2022 A Ghrelin Anamorelin SM Agonist Cancer cachexia 2020 A GPER Raloxifene SM Agonist Breast cancer 2007 A TSHR Thyrotropin Alfa Peptide Agonist Thyroid cancer 1998 C GPRC5D/CD3 Talquetamab Bispecific antibody - MM 2023 F SMO Vismodegib SM Antagonist Basal cell carcinoma 2012 F SMO Sonidegib SM Antagonist Skin cancer, basal cell carcinoma 2015 F SMO Glasdegib SM Antagonist AML 2018 Listed GPCR-targeted antineoplastic drugs Compared to traditional approaches, emerging strategies targeting GPCRs aim to overcome their inherent target complexities, such as functional pleiotropy and widespread tissue distribution, and address the challenge of “undruggability”, demonstrating unique potential. Rather than simply turning receptors “on” or “off,” these new modalities seek to modulate their activity with greater precision, degrade them entirely, or harness them as beacons for cellular therapies—offering novel ways to navigate the multidimensional regulatory landscape of the TME. Traditional ligands primarily target the orthosteric site (the native ligand-binding pocket) of GPCRs, often constrained by the conserved nature of this site, leading to insufficient selectivity and off-target effects. Allosteric modulators regulate receptor conformation and function by binding to non-orthosteric sites (allosteric sites), including positive allosteric modulators (PAMs), negative allosteric modulators, and neutral allosteric ligands [ 118 ]. As allosteric sites typically exhibit higher subtype specificity, these modulators enable more precise signaling modulation and may circumvent side effects associated with orthosteric ligands [ 119 ]. For instance, mGluR5 allosteric modulators effectively suppressed tumor cell proliferation and invasion in glioma models by modulating receptor conformation. Targeting ADGRG2 (aGPCR member), researchers employed yeast surface display to identify the nanobody Nb23-bi. This antibody binded to the ECD of ADGRG2, inducing conformational changes that significantly potentiated the signaling efficacy of the endogenous ligand DHEA (enhancing Gs/Gq pathway activation by approximately 10-fold) [ 120 ]. This work represents the first development of an allosteric nanobody for an aGPCR, providing a universal screening framework for targeting such “orphan receptors,” and establishing a critical foundation for nanobodies as allosteric modulators. Biased ligands represent another groundbreaking strategy [ 121 ]. These ligands selectively activate specific downstream signaling pathways of GPCRs (e.g., favoring G protein pathways over β-arrestin pathways, or vice versa), thereby avoiding the activation of pathways linked to adverse effects. For instance, in non-small cell lung cancer, different bile acid receptor agonists exert diametrically opposed regulatory effects on YAP activity through biased signaling pathways, subsequently influencing cellular proliferation and apoptosis [ 122 ]. This phenomenon provides a novel rationale for designing targeted therapeutics that concurrently modulate metabolism and exert anticancer activity. Furthermore, fine-tuned regulation of receptor function can also be indirectly achieved by modulating GPCR-associated signaling molecules, such as GPCR kinase 2 (GRK2). Inhibiting GRK2 facilitated the unbiased downregulation of the insulin-like growth factor 1 receptor, consequently suppressing malignant cell growth [ 123 ]. This approach offers a supplementary strategy for indirectly targeting the GPCR signaling network. By enabling pathway-specific modulation, allosteric and biased ligands offer a route to disentangle the beneficial from the detrimental effects of GPCR signaling, a critical capability given the pleiotropic roles these receptors play in different TME compartments. Targeted protein degradation represents a paradigm shift in drug design that does not rely on traditional “occupancy-driven” inhibition. Instead, it harnesses the cell’s intrinsic protein degradation machinery, primarily the ubiquitin-proteasome system and lysosomal pathways, to specifically induce pathogenic GPCR degradation, thereby eliminating their function at the source [ 124 ]. This approach is particularly applicable to “undruggable” GPCR targets that are recalcitrant to traditional small molecules. Proof-of-concept was provided by the successful development of a PROTAC molecule targeting CCR9 for degradation [ 125 ]. However, current PROTAC technology is primarily suited for cytosolic proteins, and successful degradation of transmembrane GPCRs remains relatively limited. Consequently, considerable efforts are directed toward next-generation degradation technologies, including LYTAC (lysosome-targeting chimeras), AbTAC (antibody-based PROTACs) or PROTAB (PROteolysis targeting antibody), GluTAC (glue target chimeras), and KineTAC (cytokine receptor-targeting chimeras) [ 126 ]. LYTAC utilizes cell-surface lysosome-targeting receptors (e.g., CI-M6PR) to direct target proteins to the lysosome for degradation. AbTAC/PROTAB employs bispecific antibodies that simultaneously engage a cell-surface target protein (e.g., a GPCR) and an E3 ubiquitin ligase, inducing ubiquitination and degradation of the target. GluTAC typically utilizes a covalent nanobody to bind the target protein and is linked to an E3 ligase ligand to achieve targeted degradation. KineTAC employs engineered cytokine receptors to internalize the target protein and direct it to the lysosome for degradation (Fig. 5 ). In contrast to conventional agents that rely on transient receptor occupancy, these emerging platforms function through catalyzing the selective elimination of the entire target protein rather than merely inhibiting its activity. In doing so, degradation technologies directly surmount two inherent limitations of traditional pharmacology: they circumvent resistance driven by target overexpression or mutation, while simultaneously enabling the targeting of receptors that lack conventional druggable pockets. In this manner, targeted protein degradation expands the therapeutic landscape beyond occupancy-driven constraints, providing a mechanistically orthogonal approach for engaging previously intractable GPCR targets. Fig. 5 Illustrations of the current membrane protein targeted degradation technologies. ( A ) Targeted degradation of a plasma membrane protein by a traditional proteolysis-targeting chimera (PROTAC). ( B ) Membrane protein degradation by a lysosome-targeting chimera (LYTAC). ( C ) Antibody-based PROTAC (AbTAC) and proteolysis targeting antibody (PROTAB)-mediated protein degradation. ( D ) Covalent nanobody-based degrading chimera (GlueTAC)-driven targeted degradation. ( E ) Membrane protein degradation by a cytokine receptor-targeting chimera (KineTAC). “Ub” shown in grey circles represents a single ubiquitin molecule. Adopted from Ref [ 126 ] Illustrations of the current membrane protein targeted degradation technologies. ( A ) Targeted degradation of a plasma membrane protein by a traditional proteolysis-targeting chimera (PROTAC). ( B ) Membrane protein degradation by a lysosome-targeting chimera (LYTAC). ( C ) Antibody-based PROTAC (AbTAC) and proteolysis targeting antibody (PROTAB)-mediated protein degradation. ( D ) Covalent nanobody-based degrading chimera (GlueTAC)-driven targeted degradation. ( E ) Membrane protein degradation by a cytokine receptor-targeting chimera (KineTAC). “Ub” shown in grey circles represents a single ubiquitin molecule. Adopted from Ref [ 126 ] Aberrant GPCR expression drives tumor initiation and progression. Nucleic acid therapeutics, such as small interfering RNA (siRNA), antisense oligonucleotides, and CRISPR-Cas9 gene editing tools, achieve specific downregulation or correction of pathogenic GPCR expression at the mRNA or DNA level through gene silencing or editing technologies, offering the potential to halt tumorigenesis at its root [ 127 , 128 ]. For example, siRNA targeting GPR87, delivered via PLGA nanoparticles, achieved potent silencing in pancreatic cancer cells, significantly inhibiting tumor growth and providing a novel therapeutic strategy for pancreatic cancer [ 129 ]. Furthermore, nucleic acid technologies serve not only as therapeutics but also as powerful tools for fundamental research [ 130 , 131 ]. Utilizing RNA interference (RNAi) or CRISPR-Cas9 to construct disease-mimicking cell lines and animal models enables more precise elucidation of GPCR roles in tumorigenesis and progression, supporting target validation and drug discovery. Although GPCR-targeted nucleic acid therapy development is currently limited, its potential for precise genetic targeting holds considerable future promise. Notably, strategies employing nucleic acid aptamers to directly modulate GPCR activity through allosteric mechanisms also demonstrated unique potential. For instance, a P2RY2 receptor RNA aptamer, identified via virus-like particle display technology, exhibited dual functionality depending on the receptor’s pre-binding status with its endogenous ligand: it acts as an agonist towards the ligand-unbound receptor, while functioning as a PAM that significantly potentiates the activity of the ligand-bound receptor [ 132 ]. This provides a novel rationale for the fine-tuned modulation of GPCR signaling networks. Nucleic acid technologies offer a fundamentally different approach: rather than modulating protein function, they prevent its expression altogether. This genetic-level intervention could prove particularly valuable for targets whose aberrant expression is driven by transcriptional dysregulation—a common feature in cancer. Chimeric antigen receptor T-cell therapy (CAR-T) represents an emerging immunotherapeutic approach primarily employed in cancer treatment, demonstrating significant potential, particularly in hematological malignancies [ 133 , 134 ]. The core principle involves genetically engineering autologous T cells (using viral vectors or CRISPR technology) to express chimeric antigen receptors (CARs) that specifically recognize tumor antigens. Following reinfusion, these engineered CAR-T cells bypass major histocompatibility complex (MHC) restriction, enabling direct recognition and killing of tumor cells expressing the target antigen. CAR design is critically dependent on tumor-specific antigen selection. Among these, GPRC5D has emerged as a highly promising novel target due to its elevated expression in MM [ 135 ]. A Phase II clinical trial confirmed that GPRC5D-targeted CAR-T therapy achieved an 84% ORR in patients with RRMM, demonstrating efficacy even in patients resistant to BCMA-targeted therapies [ 136 ]. Furthermore, a Phase I trial revealed that bispecific CAR-T cells co-targeting BCMA and GPRC5D elevated the ORR to 86% in RRMM patients, highlighting the considerable therapeutic potential of CAR-T approaches in this field [ 137 ]. However, CAR-T therapy still faces significant challenges in solid tumors, such as the TME suppression and target antigen heterogeneity. Consequently, novel cell therapies centered on CAR technology are rapidly emerging, including CAR-NK (natural killer cells), CAR-NKT (NKT cells), CAR-M (macrophages) [ 138 – 140 ]. These strategies leverage the unique properties of diverse immune cell types to overcome solid tumor barriers, exhibiting broad prospects within the field of cancer immunotherapy. Cellular therapies represent the ultimate embodiment of the multidimensional regulation paradigm: engineered immune cells can actively sense, migrate to, and remodel the TME, while simultaneously killing tumor cells. By leveraging GPCRs as recognition elements, these living drugs can adapt to the dynamic complexity that confounds conventional pharmacology.