Recent Advances in Cyclic Peptide-Based Therapeutic Strategies for Renal Cell Carcinoma: A Focused Review

Abstract

Renal cell carcinoma (RCC), especially clear cell RCC (ccRCC), remains difficult to control after resistance to targeted therapy or immune checkpoint blockade develops. Cyclic peptides provide conformationally constrained and chemically adaptable scaffolds for direct target modulation, tumor-selective payload delivery, radiotheranostics, supramolecular assembly, and induced-proximity pharmacology. This focused mini-review groups cyclic peptide-based strategies according to the role played by the peptide in the therapeutic system. The peptide may act as the drug itself, carry a drug or radionuclide, guide a larger carrier, assemble into a drug-delivery material, or bring two proteins together. Direct RCC evidence is anchored by carbonic anhydrase IX (CAIX)-targeted DPI-4452/ZH2 radiotheranostics, cyclic Arg-Gly-Asp (cRGD)-guided small interfering RNA (siRNA) delivery to tumor endothelium, and PB1-p62-mediated polybromo 1 (PBRM1) degradation and immune sensitization. Drug-resistant non-RCC models are retained only as transferable design evidence for efflux-evasive or self-assembling delivery. We further discuss target heterogeneity, linker and assembly stability, pharmacokinetics, renal distribution, scalable synthesis, and the experimental controls required to attribute benefit to the cyclic peptide component. Although clinical therapeutic evidence remains limited, the emerging RCC-specific studies support a mechanism-matched development strategy for this drug class.

Introduction

RCC is a common malignancy, and ccRCC accounts for the majority of histological subtypes.1 Over the past decade, targeted tyrosine kinase inhibitors (TKIs), immune checkpoint inhibitors (ICIs), and mechanistic target of rapamycin (mTOR) inhibitors have improved outcomes for patients with advanced disease. Cytotoxic chemotherapy has limited activity in most RCC subtypes.1 Although this clinical phenotype cannot be attributed to a single mechanism, ATP-binding cassette (ABC) transporters can reduce intracellular drug exposure and contribute to multidrug resistance.2 Nomura et al found that conjugated bilirubin increased multidrug resistance-associated protein 2 (MRP2) messenger RNA expression in cultured RCC specimens. In a separate experiment using renal proximal tubule epithelial cells, conjugated bilirubin increased MRP2 expression at both the messenger RNA and protein levels and reduced cisplatin sensitivity.3 Additional targets linked to post-translational regulation and immune signaling, including interferon regulatory factor 9 (IRF9), remain at an early investigational stage.4

Although TKIs have advanced the treatment of RCC, responses remain heterogeneous and acquired resistance commonly develops through alternative angiogenic signaling, reduced intracellular drug concentrations, tumor-cell plasticity, and microenvironmental adaptation.5 Treatment-related toxicity can also require dose delays or reductions and compromise treatment continuity; in a 2025 series of 96 patients receiving first-line sunitinib, dose delays and dose reductions occurred in 38.5% and 66.7% of patients, respectively.6 At the biological level, von Hippel-Lindau (VHL)-hypoxia-inducible factor (HIF) dysregulation is central to ccRCC but does not fully explain disease behavior.7 Alterations in tumor suppressors such as PBRM1 and BRCA1-associated protein 1 (BAP1) can intersect with type I interferon signaling and influence therapeutic response,8 while intratumoral heterogeneity further complicates target selection.9 These limitations support the development of therapeutic platforms that can be matched to specific molecular targets, cell populations, and delivery requirements.

Cyclic peptides are conformationally constrained molecules with strong target-binding potential, tunable stability, and substantial chemical modifiability.10 Their function depends on sequence and architecture. The intact peptide may serve as the pharmacophore,11 guide a linked payload or carrier,12 organize a supramolecular material,13 or recruit a second protein to create an induced-proximity mechanism.14 In this article, cyclic peptide-based therapeutic strategies therefore refers to platforms in which a confirmed cyclic peptide serves as an active agent, targeting ligand, assembly unit, payload-bearing scaffold, or bifunctional recognition element. Consistent with the focused mini-review format, we highlight selected recent advances and distinguish direct RCC evidence from design principles established in other tumor models.

Therapeutically Relevant Properties of Cyclic Peptides

The therapeutic value of cyclic peptides arises from their ability to restrict backbone conformation while retaining a relatively large surface for molecular recognition. By favoring binding-competent conformations, cyclization can support high-affinity and selective recognition of shallow or extended protein surfaces that are difficult to address with conventional small molecules. In a representative Random nonstandard Peptides Integrated Discovery (RaPID) screening study, N-methylated macrocycles were selected against the ubiquitin ligase E6-associated protein (E6AP), and one peptide inhibited E6AP-dependent protein ubiquitination.15 A later messenger ribonucleic acid (mRNA)-display study identified the cyclic calcium and integrin-binding protein 1 (CIB1) ligand UNC10245131, which showed low-nanomolar affinity, selectivity over related EF-hand proteins, and improved permeability and stability relative to the previously identified linear inhibitor UNC10245092. However, UNC10245131 did not exhibit cytotoxicity or alter the downstream signaling examined in that study.16 These findings illustrate the potential of cyclic peptides to engage protein-protein interaction surfaces, although affinity and functional activity remain sequence- and target-dependent.17

Pharmacokinetic advantages are likewise tunable rather than intrinsic to every cyclic scaffold. Cyclization can remove exposed termini and reduce protease access, whereas cellular entry depends on peptide size, backbone hydrogen-bond exposure, side-chain composition, lipophilicity, and the ability to adopt different conformations across aqueous and membrane environments. Backbone rigidification and fixed presentation of guanidinium groups increased uptake in an arginine-rich peptide series.18 Hosono et al further showed that selected amide-to-ester substitutions increased membrane permeability while retaining serum or plasma stability, and that their effects differed from those of N-methylation.19 At a translational level, multiparameter optimization of bi- and tricyclic proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors produced compounds that achieved oral exposure in rats and cynomolgus monkeys using an enabling formulation; target engagement and low-density lipoprotein cholesterol lowering were demonstrated in cynomolgus monkeys.20 More recently, small backbone changes in sanguinamide A analogues produced substantial differences in permeability, polarity-dependent conformation, and cellular phenotypes.21 These studies show that stability, permeability, and oral exposure must be optimized for each scaffold.

A second advantage is chemical programmability. Defined residues or synthetic handles support the modular preparation of cyclic peptide conjugates and other functionalized formats.10 In RCC models, this flexibility has enabled recognition of the tumor-associated surface target carbonic anhydrase IX (CAIX),22 delivery of small interfering RNA to tumor vasculature,23 and engagement of intracellular proteins through a bifunctional scaffold.14 Conjugation and formulation can also change proteolytic stability, circulation time, tissue retention, and clearance.24 Target selectivity, payload activity or release, systemic exposure, and distribution in both tumor and normal kidney should therefore be evaluated together. These properties underpin the functional formats examined below: direct-acting agents, payload-bearing conjugates and radioligands, peptide-decorated carriers, self-assembling systems, and bifunctional induced-proximity constructs. The overall evidence landscape and key requirements for RCC translation are summarized in Figure 1, while representative platforms and their level of RCC evidence are detailed in Table 1

Figure 1.

Main types and evidence landscape of cyclic peptide-based therapeutic strategies relevant to renal cell carcinoma (RCC). (A) CAIX-targeted cyclic peptide radiotheranostics, exemplified by DPI-4452 and ZH2, enable PET imaging and targeted radionuclide therapy through recognition of tumor-associated CAIX. (B) Peptide-guided delivery systems use cRGD-decorated carriers to target tumor endothelium and deliver siRNA against VEGFR2 or biglycan, resulting in vascular modulation. (C) Bifunctional induced-proximity peptides, represented by PB1-p62, promote PBRM1 recruitment to p62-associated degradative machinery and subsequent PBRM1 degradation. (D) Direct-acting cyclic peptides can disrupt protein–protein interactions, as illustrated by cyclic peptide-mediated blockade of the PD-1/PD-L1 immune-checkpoint interface. (E) Cyclic peptide–drug conjugates, exemplified by P6-SN38, combine receptor recognition with intracellular delivery of a cytotoxic payload. (F) Self-assembling cyclic peptide systems form supramolecular structures that enable drug loading and controlled payload release. Panels (A–C) represent direct RCC-specific evidence, whereas panels (D–F) illustrate transferable platform evidence derived primarily from non-RCC models. Key requirements for RCC translation include target validation, delivery and formulation stability, renal distribution and safety, and scalable manufacturing.

Table 1.

Representative Cyclic Peptide-Based Therapeutic Platforms Discussed in Relation to Renal Cell Carcinoma

Cyclic Peptide or Platform	Target and Payload	Design and Mechanism	Model and Context	Main Findings	Evidence Stage and RCC Relevance
DPI-445222,25	CAIX; 68Ga for imaging or 177Lu for therapy	Cyclic CAIX-binding peptide coupled to DOTA for radiotheranostic delivery	SK-RC-52 RCC and HT-29 xenografts; three patients with metastatic ccRCC	Rapid, tumor-selective uptake; 177Lu treatment inhibited SK-RC-52 and HT-29 xenograft growth; human PET showed high tumor-to-background contrast	Preclinical therapy; first-in-human imaging and dosimetry
ZH226	CAIX; 68Ga for imaging or 177Lu for therapy	Redesigned cyclic binding motif, linker, and radiometal chelator	OS-RC-2 tumors; 21 patients, including 19 with paired FDG imaging	Reduced gastrointestinal retention; inhibited tumor growth in mice; additional lesions detected in paired human imaging	Preclinical therapy; early clinical imaging
cRGD-modified MEND or liposome12,23	Integrin αvβ3; VEGFR2 siRNA or biglycan siRNA	Carrier-surface cyclo(Arg-Gly-Asp-D-Phe-Lys) with encapsulated siRNA for tumor-endothelial delivery	OS-RC-2 xenografts and RCC tumor-endothelial-cell models	VEGFR2 or biglycan knockdown inhibited tumor growth; biglycan silencing partially normalized tumor vasculature	RCC-specific preclinical evidence
PB1-p62 bifunctional bicyclic peptide14	PBRM1 and p62; no releasable payload	Bifunctional scaffold that induces PBRM1-p62 proximity and p62-dependent PBRM1 degradation	RCC cells and Renca tumors treated with anti-PD-1	Promoted PBRM1 degradation and enhanced the antitumor activity of anti-PD-1 treatment	RCC-specific preclinical evidence
Cyclic PD-L1 inhibitors11	PD-L1; the intact peptide is the active agent	Macrocyclized peptides directly block the PD-1-PD-L1 interaction	PD-L1-positive cancer cells and CT26 tumors; no RCC model	Up to 34-fold improvement in blocking activity over the linear precursor and significant in vivo antitumor activity	Direct-acting platform evidence outside RCC
[R5K]W7A-doxorubicin29	Cellular delivery function; doxorubicin payload	Hybrid cyclic-linear peptide linked to doxorubicin through a glutarate spacer	Doxorubicin-resistant MDA-MB-231R and MES-SA/MX2 cells; no RCC efficacy model	Higher cytotoxic activity than free doxorubicin in resistant cells, with lower toxicity in renal and cardiac cell models	Transferable in vitro evidence outside RCC
P6-SN3830	EGFR; SN-38 payload	EGFR-binding cyclic peptide joined to SN-38 through a monosuccinate linker	Paired H1299 NSCLC and EGFR-negative K562 leukemia xenografts	P6-FITC accumulated in H1299 tumors; P6-SN38 inhibited H1299 growth without inhibiting K562 tumors	In vivo peptide-drug conjugate evidence outside RCC
Self-assembling CP1 or CP2-doxorubicin derivatives13	No RCC-selective target; doxorubicin payload	Hydrazone-linked conjugates with alkyl-tail variants that form cyclic peptide nanotubes	MCF-7, NCI-H460, and doxorubicin-resistant NCI/ADR-RES cells; no RCC model	Suitable alkyl tails increased activity in resistant NCI/ADR-RES cells; hydrazone cleavage remained incomplete after 72 h at pH 5.0	Transferable in vitro evidence outside RCC
Cyclic peptide-polymer-SN-38 nanotubes31	No RCC-selective target; SN-38 payload	Polymer-conjugate core bearing multiple SN-38 units with dynamic self-assembly and sustained release	CT26 colorectal tumors; no RCC model	Approximately 14 wt% SN-38 loading and sustained release; plasma exposure predominantly reflected conjugated SN-38; inhibited CT26 tumor growth	In vivo platform validation outside RCC

Notes: Evidence stage refers to the highest level represented in the cited studies. Non-RCC examples are included as transferable platform evidence and do not establish efficacy in RCC. For SN-38 nanotubes, total plasma exposure mainly reflected conjugated SN-38; free hydrolyzed SN-38 was below the detection limit. Irinotecan was included as an in vivo comparator.

Abbreviations: CAIX, carbonic anhydrase IX; ccRCC, clear cell renal cell carcinoma; DOTA, 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid; EGFR, epidermal growth factor receptor; FDG, fluorodeoxyglucose; FITC, fluorescein isothiocyanate; MEND, multifunctional envelope-type nanodevice; NSCLC, non-small cell lung cancer; PBRM1, polybromo 1; PD-1, programmed cell death protein 1; PD-L1, programmed death-ligand 1; RCC, renal cell carcinoma; siRNA, small interfering RNA; VEGFR2, vascular endothelial growth factor receptor 2.

Cyclic Peptide-Based Therapeutic Strategies Relevant to RCC

CAIX-Targeted Cyclic Peptide Radiotheranostics

In CAIX-targeted radiotheranostics, the cyclic peptide provides molecular recognition, whereas a chelator-bound radionuclide supports positron emission tomography (PET) imaging or targeted radioligand therapy, as exemplified by DPI-4452.22 Clinical evaluation additionally requires tumor residence time, biodistribution, dosimetry, and normal-tissue exposure to be considered.25

CAIX is one of the clearest molecular entry points for cyclic peptide development in ccRCC because VHL loss stabilizes HIF signaling and produces high CAIX expression in many tumors.7 DPI-4452 is a CAIX-binding cyclic peptide linked to a chelator that can be labeled with gallium-68 for PET or lutetium-177 for radioligand therapy. In preclinical studies, [68Ga]Ga-DPI-4452 showed rapid, tumor-selective uptake, and [177Lu]Lu-DPI-4452 inhibited the growth of SK-RC-52 renal cancer and HT-29 xenografts with acceptable tolerability.22

The first-in-human imaging study enrolled three patients with ccRCC and demonstrated rapid, sustained lesion uptake over four hours, high tumor-to-background contrast, and rapid renal elimination without clinically significant toxicity.25 These findings provide early clinical evidence for CAIX-directed cyclic peptide imaging and dosimetry, but do not establish therapeutic benefit from lutetium-177 treatment.

A 2026 structure-guided study addressed gastrointestinal retention associated with physiological CAIX expression. Redesign of the cyclic peptide binding motif, linker, and chelator yielded ZH2, which retained subnanomolar affinity and tumor uptake while reducing gastrointestinal background. [177Lu]Lu-ZH2 inhibited OS-RC-2 tumor growth and prolonged survival in mice, and [68Ga]Ga-ZH2 was evaluated in 21 patients with suspected primary renal tumors or recurrent ccRCC. No drug-related adverse events were observed during the 72-hour follow-up. Among the 19 patients who also underwent fluorine-18 fluorodeoxyglucose PET/computed tomography (18F-FDG PET/CT), paired imaging identified additional primary tumors and metastases with [68Ga]Ga-ZH2.26 These findings connect scaffold engineering with efficacy in an RCC model and early clinical imaging, although therapeutic clinical efficacy remains to be established.

cRGD-Guided Nanocarriers for RCC Tumor Vasculature

In this modality, a cyclic peptide is displayed on a liposome, lipid nanoparticle, or related carrier. The peptide provides receptor recognition and promotes delivery to the intended cell population, whereas the carrier controls cargo loading, stability, biodistribution, and release.12,23 cRGD-modified multifunctional envelope-type nanodevices (MENDs) provide the clearest RCC example of this division of function.

cRGD provides a verified example of a cyclic peptide used as a carrier-targeting ligand in RCC. Sakurai et al incorporated cyclo(Arg-Gly-Asp-D-Phe-Lys) into a liposomal small interfering RNA (siRNA) system to target alpha-v beta-3 integrin on tumor endothelial cells. Delivery of vascular endothelial growth factor receptor 2 (VEGFR2) siRNA produced gene silencing and antiangiogenic activity in an RCC model, establishing an early proof of concept for cyclic peptide-guided nucleic-acid delivery.12

Maishi et al subsequently used cRGD-modified MENDs to deliver biglycan siRNA to tumor endothelial cells in OS-RC-2 xenografts. Flow cytometry and tissue imaging supported preferential delivery to tumor endothelium, with low signal in normal kidney endothelium; biglycan knockdown inhibited tumor growth and partially normalized fibrosis, vessel structure, perfusion, and hypoxia.23 This study directly supports microenvironment-directed treatment in RCC, although the therapeutic experiment was small, with four mice per group, and did not test whether vascular normalization improved a standard TKI or immune-checkpoint regimen. The findings therefore establish preclinical delivery and biological activity but not clinical resistance reversal.

Bifunctional Cyclic Peptides for PBRM1 Degradation and Immune Sensitization

Bifunctional cyclic peptides contain two recognition elements that bring a target protein into proximity with an effector protein or degradation machinery. Their activity may arise from target depletion or signaling redirection.14,27 Outside RCC, a cyclic peptide-based proteolysis-targeting chimera reduced DHHC3 protein levels and programmed death-ligand 1 (PD-L1) expression in cervical cancer cells, supporting the feasibility of this architecture.27 In RCC, PB1-p62 uses recognition elements for PBRM1 and p62 to promote PBRM1 loss and modify immune responsiveness.14

Fan et al connected PBRM1 depletion to immune sensitization in Renca tumors. Ccl5 or Ccl20 silencing reduced macrophage recruitment induced by PBRM1 depletion, while macrophage removal abolished the enhancement of anti-programmed cell death protein 1 (PD-1) treatment. The study also identified cell division cycle 20 (CDC20)-associated lysine-27-linked ubiquitination and p62-dependent PBRM1 degradation. The bicyclic peptide PB1-p62 increased PBRM1-p62 association, shortened PBRM1 protein half-life, and improved anti-PD-1 activity in subcutaneous Renca tumors. Tumor and immune analyses used six mice per group, and survival analyses used twelve.14

This work is the strongest RCC-specific example of an induced-proximity cyclic peptide in the current evidence base. Nevertheless, genetic PBRM1 depletion and peptide treatment are not interchangeable interventions, and the chemokine dependency demonstrated after knockdown should not automatically be assigned to every effect of PB1-p62. The relative contributions of autophagic and proteasomal routes also remain incompletely resolved in the reported experiments.14 Further studies should test human ccRCC models, define biomarkers for productive engagement of PBRM1 and p62, and determine whether sustained PBRM1 depletion is beneficial across different immune contexts.

Emerging Direct-Acting, Drug-Conjugate, and Self-Assembling Platforms

In direct-acting platforms, the intact cyclic peptide is the active agent and engages an extracellular interaction or an intracellular protein interface.17 Cyclic peptide inhibitors of PD-L1 illustrate direct blockade of an immune-checkpoint interface.11 A fungi-derived cyclic peptide has also been reported to enhance T helper 9 cell-mediated antitumor immunity in a non-RCC model.28 In RCC, VHL-HIF signaling provides one possible source of difficult protein interfaces.7 However, any proposed direct inhibitor must demonstrate target engagement, intracellular exposure when required, and disease-specific efficacy.

In cyclic peptide-drug conjugates, the peptide is covalently linked to a pharmacologically active payload, and performance depends on target recognition, internalization, spacer chemistry, and preservation or release of payload activity.29,30 Mozaffari et al linked doxorubicin to the hybrid cyclic-linear peptide [R5K]W7A through a glutarate spacer. The conjugate was approximately 16-fold and 9.5-fold more cytotoxic than free doxorubicin in resistant MDA231R and MES-SA/MX2 cells, respectively, while showing lower toxicity in LLC-PK1 renal epithelial and H9C2 cardiac cells.29 More recently, the epidermal growth factor receptor (EGFR)-targeting cyclic peptide conjugate P6-SN38 used a monosuccinate linker. Fluorescein isothiocyanate-labeled P6 (P6-FITC) preferentially accumulated in H1299 non-small cell lung cancer xenografts compared with contralateral EGFR-negative K562 leukemia xenografts. In a separate treatment experiment using the same paired model, P6-SN38 inhibited H1299 tumor growth without inhibiting the K562 tumors.30 These studies provide transferable evidence for target selection and linker design, but their activity in RCC remains to be tested.

Self-assembling cyclic peptides use the peptide as both a molecular scaffold and a building unit for higher-order drug-delivery structures. Alternating D/L peptides can stack through backbone hydrogen bonding to form nanotube-like assemblies, and therapeutic performance depends on drug loading, assembly stability, release, cellular trafficking, and clearance.13,31

Vilela-Picos et al evaluated self-assembling cyclic peptide-doxorubicin conjugates in MCF-7, NCI-H460, and doxorubicin-resistant NCI/ADR-RES cells. In resistant NCI/ADR-RES cells, suitable alkyl-tail modifications increased activity relative to poorly active tailless conjugates, and uptake experiments supported an important role for endocytosis. Hydrazone cleavage remained incomplete after 72 hours at pH 5.0; the authors proposed that persistence of the peptide-drug linkage could help limit drug efflux during intracellular trafficking.13 More recently, cyclic peptide-polymer nanotubes carrying multiple SN-38 units achieved approximately 14 wt% drug loading, sustained release, prolonged total plasma SN-38 exposure, and antitumor activity in a CT26 colorectal tumor study that included irinotecan as a comparator. The plasma measurements primarily reflected nanotube-bound SN-38, while free hydrolyzed SN-38 was below the detection limit.31 Together, these studies show how cyclic peptide architecture can alter exposure, trafficking, and release. Their role in this review is to define testable design principles for drug-resistant RCC rather than to establish RCC efficacy.

Translational Opportunities and Challenges for RCC-Oriented Cyclic Peptide-Based Therapeutics

The development of cyclic peptide-based therapeutics for RCC should proceed from mechanistic proof of concept toward target-specific and pharmacologically optimized systems. Nucleotide-encoded macrocyclic peptide libraries provide access to large and chemically diverse search spaces,32 while site-specific incorporation of an electrophilic noncanonical amino acid has recently enabled the selection of target-specific covalent macrocyclic binders.33 The progression from DPI-4452 to ZH2 further shows that structure-guided redesign can reduce a clinically visible biodistribution liability while retaining the targeting scaffold.26 Candidate molecules should be prioritized according to tumor-selective target expression, affinity, internalization or intracellular access, and compatibility with the intended payload, carrier, assembly, or induced-proximity mechanism.

For RCC, platform selection should follow the biological problem being addressed. Direct-acting cyclic peptides can block extracellular protein interactions, as illustrated by PD-L1 inhibitors.11 CAIX-targeted radioligands can link molecular imaging with patient selection and targeted radiation.25,26 cRGD-decorated carriers can deliver nucleic acids to tumor vasculature,23 whereas PB1-p62 illustrates induced-proximity pharmacology.14 Future platforms should be linked to a defined RCC dependency, cell population, or resistance mechanism, and the contribution of the cyclic peptide should be tested with appropriate controls.

Despite these opportunities, pharmacokinetic optimization remains a major barrier. Peptide-based drugs may be limited by proteolytic degradation, short systemic half-life, poor membrane permeability, or rapid clearance. D-amino acid substitution, N-methylation, lipidation, polyethylene glycol conjugation, albumin fusion, and nanoparticle or liposomal formulation can improve stability or exposure, but the effect is scaffold-dependent.24 Renal handling is especially important in RCC. DPI-4452 showed rapid renal elimination in patients,25 whereas structure-guided redesign of ZH2 reduced off-target gastrointestinal retention.26 Pharmacokinetic improvement should therefore be evaluated together with tumor accumulation, normal-kidney distribution, and toxicity in renal epithelial models.

Manufacturing feasibility is another important issue. Natural and synthetic cyclic peptides may require demanding cyclization, purification, and structural-confirmation procedures; inefficient cyclization can limit yield, while solvent-intensive synthesis and purification can complicate industrial scale-up.34 Complexity increases further when peptides are coupled to linkers and payloads, displayed on carrier surfaces, or engineered to self-assemble. Translational studies should report the synthetic or formulation route, conjugation or loading efficiency, batch reproducibility, purity, stability, and scalability. Without these data, promising platforms may remain difficult to advance beyond laboratory-scale validation.

For cyclic peptide-drug conjugates, linker and spacer chemistry can determine whether target recognition is converted into cytotoxic activity. A glutarate spacer was used to join doxorubicin to [R5K]W7A,29 whereas P6-SN38 used a monosuccinate linker.30 In a self-assembling doxorubicin system, incomplete hydrazone cleavage at acidic pH indicated persistent peptide-drug linkage, which the authors proposed could help evade efflux.13 This finding illustrates the need to evaluate linkage stability together with intracellular trafficking and activity, rather than assuming that faster release is always preferable. For peptide-decorated carriers, receptor-dependent delivery, formulation, and biodistribution must be evaluated;12,23 for self-assembling systems, cargo loading, assembly stability, release kinetics, and systemic exposure are additional determinants.31 Each platform therefore requires a mechanism-matched workflow covering plasma stability, tumor uptake, intracellular disposition, pharmacodynamic activity, antitumor efficacy, and renal safety.

Overall, the most credible development path is to match the cyclic peptide’s function to a validated RCC target or biological compartment. Direct-acting peptides require target engagement; conjugates and radioligands require an appropriate payload, linker or chelator, and dosimetry where relevant; decorated carriers require reproducible formulation and receptor-dependent delivery; self-assembling systems require control of supramolecular behavior; and bifunctional peptides require productive engagement of both partners. Comparisons with matched noncyclic ligands, untargeted carriers, free payloads, and inactive bifunctional controls are essential to determine whether the cyclic peptide component adds therapeutic value.

Conclusions

Cyclic peptide-based therapeutics provide several routes into RCC biology. Grouping the evidence according to peptide function distinguishes direct-acting agents, payload conjugates and radioligands, peptide-decorated carriers, self-assembling materials, and bifunctional induced-proximity constructs. Within this framework, CAIX-targeted DPI-4452 and ZH2 establish the strongest translational trajectory, cRGD-MEND systems provide direct preclinical evidence for tumor-endothelial nucleic-acid delivery, and PB1-p62 demonstrates immune sensitization through targeted PBRM1 degradation.

The evidence remains uneven. Clinical data currently demonstrate imaging feasibility rather than therapeutic benefit; cRGD and PB1-p62 studies remain preclinical; and the efflux-evasive or self-assembling delivery studies were performed outside RCC. Future work should prioritize disease-relevant target validation, matched platform controls, pharmacokinetics, dosimetry where applicable, renal distribution and safety, scalable manufacturing, and testing in clinically representative RCC models. These studies identify promising but still investigational cyclic peptide-based approaches for RCC whose therapeutic value requires validation in disease-relevant models and prospective clinical studies.

Funding Statement

This research was supported by the Liaoning Provincial Department of Science and Technology, General Program, 2025 Joint Science and Technology Plan Project (No. 5021342), the Dalian Life and Health Guidance Program Project (No. 2024ZDJH01PT068), and the Liaoning Revitalization Talents Program (Grant No. CL001279).

Abbreviations

18F-FDG, fluorine-18 fluorodeoxyglucose; ABC, ATP-binding cassette; ATP, adenosine triphosphate; BAP1, BRCA1-associated protein 1; CAIX, carbonic anhydrase IX; ccRCC, clear cell renal cell carcinoma; CDC20, cell division cycle 20; CIB1, calcium and integrin-binding protein 1; cRGD, cyclic Arg-Gly-Asp; E6AP, E6-associated protein; EGFR, epidermal growth factor receptor; FITC, fluorescein isothiocyanate; HIF, hypoxia-inducible factor; ICI, immune checkpoint inhibitor; IRF9, interferon regulatory factor 9; ISGF3, interferon-stimulated gene factor 3; MEND, multifunctional envelope-type nanodevice; mRNA, messenger ribonucleic acid; MRP2, multidrug resistance-associated protein 2; mTOR, mechanistic target of rapamycin; PBRM1, polybromo 1; PCSK9, proprotein convertase subtilisin/kexin type 9; PD-1, programmed cell death protein 1; PD-L1, programmed death-ligand 1; PET/CT, positron emission tomography/computed tomography; RaPID, Random nonstandard Peptides Integrated Discovery; RCC, renal cell carcinoma; siRNA, small interfering RNA; TKI, tyrosine kinase inhibitor; VEGFR, vascular endothelial growth factor receptor; VEGFR2, vascular endothelial growth factor receptor 2; VHL, von Hippel-Lindau.

Data Sharing Statement

Data availability is not applicable to this article as no new data were created or analyzed in this study.

Author Contributions

All authors made a significant contribution to the work reported, whether that is in the conception, study design, execution, acquisition of data, analysis and interpretation, or in all these areas; took part in drafting, revising or critically reviewing the article; gave final approval of the version to be published; have agreed on the journal to which the article has been submitted; and agree to be accountable for all aspects of the work.

Disclosure

The authors declare that they have no competing interests in this work.