Multifunctional Roles of Peptides in Cancer Therapy

Peptides have a lower affinity in the body and a shorter half-life as compared to antibodies. In contrast, peptides are more effective than antibodies at tissue penetration and cellular internalization. Regardless of the advantages and disadvantages of peptides, they have been used as tumor-homing ligands for the delivery of carriers (e.g., nanoparticles, extracellular vesicles, and cells) and cargoes (e.g., cytotoxic peptides and radioisotopes) to tumors. In addition, tumor-homing peptides have been bound to cargoes such as small molecules or chemotherapeutic agents via linkers to synthesize peptide-drug conjugates. In addition, peptides selectively bind to cell surface receptors and proteins, such as immune checkpoints, receptor kinases, and hormone receptors, and subsequently block their biological activity or are used as hormone analogues. In addition, peptides that enter the cell bind to proteins inside the cell and interfere with protein-protein interactions. Therefore, peptides have great potential for application as multifunctional players in cancer therapy.

Compared to antibodies, peptides have certain disadvantages, such as lower affinity, faster excretion from the body (or shorter half-life in the body), and susceptibility to protease-mediated degradation. Conversely, peptides have advantages over antibodies, including deep tissue penetration, efficient internalization into cells, lower immunogenicity and toxicity to the bone marrow and liver, and ease of modification by chemical methods. Currently, there are more than 80 peptide therapeutics on the market, including glucagon-like peptide-1 liraglutide for the treatment of type 2 diabetes and leuprolide, a somatostatin analogue for the treatment of prostate cancer. In addition, peptide drugs are used to identify peptide-mimetic epitopes, produce vaccines, and map protein-protein interaction epitopes. This article focuses on the versatile application of peptides in targeted therapy. Peptides can deliver carriers (e.g., nanoparticles, extracellular vesicles (EVs), and cells) and cargoes (e.g., cytotoxic peptides, radioisotopes, and small molecules) to target cells. inhibition or antagonism of cell surface receptors and proteins. and interfere with intracellular protein-protein interactions.  

Tumor-Homing Peptide as a Targeting Ligand

Peptide-Targeted Nanoparticle Delivery

Tumor-homing peptides have been used to direct nanoparticles to cancer cells through direct interactions between peptides and cell surface receptors or binding partners. In general, they are designed to be tumor cell specific to enhance the internalization of nanoparticles into tumor cells. The multivalent labeling of peptides on nanoparticles increases the binding affinity of peptides. In addition, the binding of peptides to nanoparticles often protects peptides from protease-mediated degradation. The most well-known tumor-homing peptides are RGD peptides, including RGD4C (ACDCRGDCFCG) and Cilengitide (RGDfV), which bind to αvβ3 integrins overexpressed in angiogenesis endothelial cells of tumor blood vessels, thereby inhibiting angiogenesis. The binding of RGD peptides to drug- or drug-loaded nanoparticles has been well studied in cancer therapy. Internalized RGD or iRGD (CRGDR/KGPDC) is a modified version of the RGD peptide that not only binds to αV integrin, but also increases the tissue permeability of the drug. Binding of the RGD motif to αV integrins expressed in tumor endothelial cells induces protease-mediated cleavage of iRGD peptides, yielding two peptides, CRGDR/K and GPDC. Subsequently, the CRGDR/K peptide containing the C-terminal CendR motif (R/KXXR/K) binds to neurocilidin-1 and activates the endocytic pathway. As a result, iRGD increases the tissue permeability of the drug, whether in combination with or co-administered to the drug.

Table.1 Integrins related products at Creative Peptides.

The mitochondrial protein p32 or gC1qR is overexpressed in tumors and is aberrantly expressed on the cell surface in tumor cells, tumor lymphatic system, and some myeloid cells such as tumor-associated macrophages (TAMs). When bound to p32-bound LyP-1 peptide (CGQKRTRGC), nanoparticle albumin-bound paclitaxel Abraxane accumulates in tumor tissue and inhibits tumor growth more effectively than non-targeted Abraxane. Vascular endothelial growth factor receptor 2 (VEGFR-2) is mainly expressed on the surface of tumor endothelial cells. Paclitaxel nanoparticles bind to VEGFR-2 binding peptide K237 peptide (HTMYYHHYQHHL) to effectively inhibit angiogenesis and induce tumor endothelial cell apoptosis and tumor tissue necrosis. The interleukin 4 receptor (IL4R), specifically type II IL4R, consists of IL4Rα and IL13Rα1, and it is upregulated in major tumors such as breast, lung, head and neck tumors, and glioblastoma compared to the corresponding control tissues. IL4RPep-1 peptide (CRKRLDRNC) is an IL4R-binding peptide that enhances the delivery of nanoparticles to IL4R-overexpressing tumors. In addition, IL4R is highly expressed in M2-polarized pro-tumor TAMs compared to M1-polarized anti-tumor macrophages, making IL4R a potential target for TAM-targeted drug delivery. The mannose receptor CD206 is also considered a cell surface marker for M2 macrophages. Nanoparticles labeled with mUNO peptide (CSPGAK), a CD206-binding peptide, facilitate selective drug delivery to M2-type TAMs and induce macrophage phenotype reprogramming from M2 to M1.

Table.2 Fibronectin Fragments / RGD Peptides at Creative Peptides.

Peptide-Targeted Delivery of EVs or Exosomes

EVs, or exosomes, are endogenous nanoparticles that are secreted into the circulation from cells. They can carry DNA, RNA, proteins, and lipids and distribute them between cells. Labeling tumor-homing peptides on the surface of therapeutic-loaded exosomes can reduce major adverse side effects in cancer therapy. Surface modification of exosomes is carried out by two methods: genetic engineering and non-genetic engineering. Using genetic engineering, dendritic cells (DCs) have been engineered to secrete exosomes expressing Lamp2, an exosomal membrane protein fused to a neuron-specific RVG peptide (YTIWMPENPRPGTPCDIFTNSRGKRASNG), which is subsequently used to target γ-aminobutyric acid (GABA) receptors to deliver short interfering RNAs to neurons, microglia, and oligodendrocytes in the brain and induce knockout of target genes. Non-specific uptake in other tissues is negligible. Similarly, mouse immature dendritic cells were genetically engineered to secrete exosomes expressing the Lamp2 protein fused to the iRGD peptide (CRGDR/KGPDC) and showed highly efficient targeted drug delivery to αv integrin-positive breast cancer cells, thereby inhibiting tumor growth. Genetically engineered, cellular exosomes expressing the platelet-derived growth factor receptor transmembrane domain fused to GE11 peptide (YHWYGYTPQNVI), an epidermal growth factor receptor (EGFR)-binding peptide, selectively deliver let-7a microRNA to breast cancer tissues. In addition, genetically engineered tumor cell-derived exosomes expressing pH-sensitive fusion GALA peptide (WEAALAEALAEALAEHLAEALALEALAA) efficiently deliver tumor antigens into the cytoplasm of dendritic cells and promote dendritic formality through major histocompatibility complex class I molecules.

Tumor Antigen Presentation of Cells

The exosome surface has also been non-genetically modified using lipid membrane anchors, electrostatic interactions, and ligand-receptor interactions. M1 macrophage-derived exosomes are transfected with NF-κBp50 siRNA and miR-511-3p to promote M1 polarization, and surface modified with IL4R-targeting IL4RPep-1 peptide using phospholipid anchors. These constructs inhibit tumor progression by reprogramming IL4R-high and M2-polarized TAMs to M1-like phenotypes. By interacting with transferrin receptors, surface modification of blood exosomes with transferrin-coupled superparamagnetic nanoparticles, surface modification with L17E endosolytic peptide through electrostatic interaction, and surface modification with cholesterol-conjugated miR-21 inhibitor anchored to lipid membranes can increase tumor accumulation and drug delivery, and achieve efficient endosomal escape. Surface-labeled exosomes with chimeric peptides containing an alkyl chain (C16), a photosensitizer (protoporphyrin IX), and a nuclear localization signal peptide can enhance the nuclear delivery of photosensitizers and effectively inhibit tumor growth by photodynamic therapy.

Peptide-Guided Cellular Delivery

In adoptive cell therapy, there is a high demand for tumor-homing to enhance cytotoxic T lymphocytes (CTLs). Therefore, chimeric antigen receptor (CAR)-T cells have been used to address this limitation. CAR-T cells are genetically modified to express chimeric receptors consisting of antibodies against tumor antigens (e.g., CD19), cytoplasmic domains of the T cell receptor zeta chain, and costimulatory domains. Conversely, non-genetic modification of the cell surface can reduce the risk of accidents caused by the genetic engineering of the cell. CTLs labeled with IL4R-binding IL4RPep-1 peptide using phospholipid-based membrane anchors exhibit enhanced tumor-homing and antitumor growth activity in mice bearing B16F10 melanoma. In addition to CTL, mesenchymal stem cells (MSCs) bound to E-selectin-targeting peptide on the cell surface exhibit controlled adhesion and rolling through interactions between peptides on stem cells and E-selectin on endothelial cells. In addition, non-genetic surface modification of MSCs using polyacrylamide linkers and biotin/streptavidin interactions to bind to sialic acid LewisX carbohydrates was shown to roll strongly on the endothelium and homing to inflamed tissues more effectively in vivo than unlabeled MSCs.

Peptides Target Cytotoxic Peptides

Cationic amphiphilic peptides with intrinsic cytotoxicity have the following advantages: they can attenuate multidrug resistance in tumor cells and have broad-spectrum antitumor activity. Conversely, they also have drawbacks, including poor membrane permeability, suboptimal therapeutic activity, and structural instability. A typical example is the KLAKLAKKLAKLAK or (KLAKLAK)2 pro-apoptotic peptide, which was originally developed as an antimicrobial peptide. In mammalian cells, it triggers mitochondrial membrane destruction and cytochrome C release, which subsequently induces apoptosis. The (KLAKLAK)2 peptide encapsulated in mesoporous nanoparticles induces mitochondrial swelling and apoptosis. The combination of (KLAKLAK)2 peptide and CNGRC peptide targeting aminopeptidase N effectively inhibits tumor growth by targeting enzymes in angiogenesis tumor endothelial cells. The IL4RPep-1 peptide (CRKRLDRNC)-fused (KLAKLAK)2 peptide conjugated to IL4R exhibits selective cytotoxicity to IL4R-expressing tumor cells and enhances the sensitivity of cells to chemotherapy. IL4R-targeting (KLAKLAK)2 peptide acts on IL-4R-high and M2-polarized TAMs as well as tumor cells, and reduces the proportion of M2-type TAMs in the tumor microenvironment, in addition, CD44v6-binding peptides (CNLNTIDTC and CNEWQLKSC), Her-2-binding peptides (YCDGFYACYMDV), prostate tumor targeting peptides (SMSIARL), and bladder tumor targeting peptides (CSNRDARRC)-guided (KLAKLAK)2 peptide can effectively inhibit tumor growth with minimal effect on normal tissues.

Peptide-Targeted Radioactive Nuclides

Peptide receptor radionuclide therapy (PRRT) involves the use of tumor-homing peptides conjugated with radioactive nuclides or isotopes as therapeutic agents. The advantages of PRRT include its selectivity in delivering radioactive nuclides, thereby reducing systemic side effects, and its effective control over advanced, inoperable, or metastatic tumors. however, radiation-induced toxicity to healthy organs (especially bone marrow) remains a major limitation. Octreotide (FCFWKTCT), an octameric peptide analogue of somatostatin, plays a crucial role in the treatment of neuroendocrine tumor patients. PRRT combined with octreotide aims to selectively irradiate neuroendocrine tumor cells expressing somatostatin receptor 2 (SSTR2) and their surrounding vasculature to inhibit angiogenesis during therapy. 111In is conjugated with octreotide using diethylenetriaminepentaacetic acid (DTPA), while 90Y and 177Lu are conjugated with DOTA as chelating agents. In addition to SSTR2, PRRT has been extended to other receptors, such as gastrin-releasing peptide (GRP) and cholecystokinin-2 (CCK-2) receptors. 99mTc-labeled RP527 peptide (VPLPAGGGTVLTKMYPRGNHWAVGHLM), a GRP analogue, has been used in the treatment of human malignancies, including colon cancer and prostate cancer. 111In-labeled minigastrin (LEEEEEAYGWMDF), a CCK-2 receptor-selective peptide, has been used in the treatment of human colorectal cancer and pancreatic tumors.

Peptide-Drug Conjugates

Peptide-drug conjugates (PDCs) are composed of three elements: tumor-homing peptides, linkers, and cytotoxic agents. Small-molecule cytotoxic agents have advantages such as high oral bioavailability, metabolic stability, and high membrane permeability, but they have high toxicity, poor solubility, and low selectivity compared to alternative drugs. By delivering PDCs to tumor cells via the tumor-homing peptide, they can exert their tumor-killing effect in the intracellular compartments of tumor cells, where tumor-specific pH or enzymes can degrade the linker and release the drug. Given that PDCs increase the local concentration of cytotoxic drugs in tumor tissues, they can reduce cytotoxic effects on normal tissues and enhance therapeutic efficacy. For antibody-drug conjugates (ADCs), it is expected that by 2026, their market size (based on revenue) will exceed $16 billion. Compared to ADCs, PDCs have better tumor penetration due to their smaller molecular weight, lower systemic exposure (due to rapid clearance from the body), lower immunogenicity, and reduced risk of liver damage. Additionally, the production methods for PDCs are easier and cheaper.

Various linkers have been designed to attach drugs or cytotoxic agents to tumor-homing peptides. Choosing the appropriate linker is critical for designing PDCs. The microenvironment in which the PDC operates should also be considered, as the linker can influence drug efficacy or binding affinity depending on structural differences. For example, certain types of peptide linkers are designed to be cleaved by abundant enzymes in tumor cells to selectively release the drug to these cells. These linkers include the GFLG peptide cleavable by cathepsin B, the PLGLAG peptide cleavable by matrix metalloproteinases (MMP)-2/9, and the oxime-hydrazone bond that can hydrolyze under acidic pH.

Octreotide, which binds to SSTR2, is conjugated to doxorubicin through a cleavable disulfide bond for the treatment of pituitary, pancreatic, and breast tumors. The disulfide bond can be cleaved by reduced glutathione (GSH) in the cell. The RGD4C peptide, which binds to αvβ3 integrin, is conjugated to the MEK1/2 inhibitor PD0325901 via a GGGGG peptide linker, enhancing its antitumor activity against glioblastoma. The RGDfK peptide-camptothecin conjugate, linked through a Lys spacer, enhances cytotoxicity against melanoma and non-small cell lung cancer cells. The GE11 peptide, which binds to EGFR, is conjugated to doxorubicin through a disulfide bond for liver cell tumors. The vascular peptide-2 conjugated to paclitaxel via a succinyl group (named ANG1005) targets low-density lipoprotein receptor-related protein-1 (LRP-1) and is applied in the treatment of gliomas and metastatic breast cancer. The FDA is considering the approval of several PDCs for commercial use. For example, BT8009, which includes a bicyclic peptide (CP(1Nal) dCM(hArg)DWSTP(HyP)WC) as the targeting part and monomethyl auristatin (MMAE) as the payload, targets Nectin-4 on tumor cells. This PDC is currently in Phase I/II clinical trials for the treatment of metastatic non-small cell lung cancer.  

Table.3 Peptides and Linkers for PDCs.

Peptide Inhibitors or Cell Surface Protein Antagonists

Immune Checkpoint Inhibitors

The emergence of immune checkpoint inhibitors (ICIs) has revolutionized the field of cancer therapy and spurred the development of more immune checkpoint blocking agents. ICIs work by blocking the interaction between immune checkpoint proteins such as CTLA-4, PD-1, and PD-L1 and their ligands, thus releasing the inhibitory brakes on T cells and leading to a strong activation of immune responses. For example, CTLA-4 is an inhibitory receptor predominantly expressed on T cells that suppresses T cell activity and is upregulated during T cell activation. Currently, ICIs are used as a first-line treatment for various solid tumors. In recent decades, antibody drugs have been widely applied as ICIs. Ipilimumab was the first CTLA-4 blocking antibody approved by the U.S. FDA for the treatment of human cancers. Anti-PD-1 antibodies like pembrolizumab and nivolumab are the second generation of antibodies approved for treating human malignant tumors, followed by anti-PD-L1 antibodies such as atezolizumab, durvalumab, and avelumab.

PD-L1 is often upregulated in the tumor microenvironment as well as in dendritic cells, macrophages, myeloid-derived suppressor cells (MDSCs), and regulatory T cells. PD-L1 interacts with its ligand PD-1. Although T cells recognize and kill tumor cells in the body, the interaction between PD-1 on T cells and PD-L1 on tumor cells leads to T cell exhaustion. Peptides have been identified that can block the PD-1/PD-L1 interaction and restore T cell activity against tumor cells. These peptides include CLP001 (HYPERPHANQAS), CLP002 (WHRSYYTWNLNT), and PD-L1Pep-1 (CLQKTPKQC)/PD-L1Pep-2 (CVRARTR). In addition to inducing T cell reactivity via PD-L1 blockade, PD-L1-binding peptides can also use PD-L1 as a tumor target for the targeted delivery of chemotherapy drugs to PD-L1 high tumors. For example, PD-L1Pep-2 peptide-labeled doxorubicin liposomes are more effective in increasing the CD⁸⁺ T cell/regulatory T cell ratio in mouse colon tumor tissues compared to PD-L1Pep-2 peptide and non-targeted doxorubicin liposome combination therapy. Prodrug nanoparticles synthesized by conjugating PD-L1Pep-2 with doxorubicin via a protease B cleavable peptide linker (FRRG) inhibit tumor progression in the 4T1 mouse breast tumor model by inducing immunogenic cell death and blocking PD-L1. Moreover, peptide conjugation to nanoparticles increases the binding affinity of the peptide. For instance, ferritin nanocages containing multivalent PD-L1Pep-1 peptides exhibit a higher binding affinity to PD-L1 compared to free PD-L1Pep-1 (~30nM vs. 300nM).

Recently, there has been increasing interest in peptides targeting next-generation immune checkpoints such as T-cell immunoglobulin and mucin domain-3 (TIM-3), lymphocyte activation gene-3 (LAG-3), and T-cell immunoreceptor with Ig and ITIM domains (TIGIT). TIM-3-binding peptides (GLIPLTTMHIGK) interfere with the binding of TIM-3 to its major ligand Gal-9, thus enhancing T cell activity. When combined with PD-L1 inhibitors, this peptide shows tumor suppression in mouse models. The cyclic LAG-3-binding peptide (CVPMTYRAC) linked by a disulfide bond interferes with the binding of LAG-3 to its major ligand HLA-DR, activating CD⁸⁺ T cells while reducing the proportion of regulatory T cells. The D-type TIGIT-binding peptide (GGYTFHWHRLNP), identified by phage display, exhibits proteolytic resistance and prolonged half-life, blocking the interaction of TIGIT with its receptor CD155 (also known as the poliovirus receptor), enhancing CD⁸⁺ T cell function and inhibiting tumor growth.

Peptide Antagonists of Tyrosine Kinase Receptors and Surface Proteins  

Tumor cells often overexpress growth factor cell surface receptors. Therefore, receptor blockers or antagonistic antibodies and peptides can be used as anti-cancer agents. c-Met is a receptor tyrosine kinase that is overexpressed in many tumors. It binds to hepatocyte growth factor (HGF) and plays a crucial role in tumorigenesis and metastasis. Using computational simulations, new peptide sequences, including CM7 (DQIIANN), were designed to bind c-Met with high affinity. This novel peptide binds to c-Met expressing cells, inhibiting c-Met-mediated cell migration, invasion, and tumor progression in mice. The disulfide-bound HGF-binding peptide, HB10 (VNWVCFRDVGCDWVL), inhibits the HGF-c-Met interaction. Soluble heparin-binding epidermal growth factor (sHB-EGF) is another target for combating cancer tumorigenesis and metastasis. Using phage display technology, two sHB-EGF-binding peptides, DRWVARDPASIF and TVGLPMTYYMHT, have been identified. These peptides inhibit sHB-EGF's promotion of ovarian tumor cell migration and invasion by suppressing the EGFR signaling pathway. 

CD44 is a cell surface receptor involved in cell adhesion to the extracellular matrix. While CD44 is expressed in normal cells, its splice variant isoform (including CD44v6) is upregulated in tumor cells, where it promotes tumor cell migration and metastasis through interaction with c-Met. By structural analysis, a peptide, v6pep (KEQWFGNRWHEGYR), was screened from the human CD44v6 domain, which interacts with c-Met and inhibits tumor growth and metastasis in a pancreatic cancer model. Currently, v6pep is undergoing clinical trials. Phage display screening of random peptide libraries has identified peptides such as NLN (CNLNTIDTC) and NEW (CNEWQKLSC) that bind to CD44v6-expressing cells, blocking HGF-mediated c-Met activation, thereby inhibiting tumor cell migration and invasion in tumors with high CD44v6 expression.

Certain tumor-derived exosomes contain heat shock protein 72 (Hsp72) on their membrane, which interacts with Toll-like receptor 2 (TLR2) on MDSCs, activating the cells. The A8 peptide (SPWPRPTY) blocks the interaction between Hsp72 and TLR2, thereby inhibiting MDSC activation and tumor progression, while enhancing the anti-tumor effect of chemotherapy drugs such as cisplatin. Therefore, peptides as cell surface protein antagonists hold great potential as tools for inhibiting tumor progression and metastasis, either used alone or in combination with chemotherapy. 

Peptide Antagonists of Hormone Receptors

Some cancers depend on hormone growth, and therefore blocking the effects of hormones can slow down or control cancer growth. This therapy is known as hormone therapy or endocrine therapy. Currently, hormone therapy is used for certain types of cancers, such as breast cancer and prostate cancer. Hormone therapy is used as an adjuvant treatment before surgery or radiation therapy to shrink the tumor size and reduce the risk of recurrence.

Gonadotropin-releasing hormone (GnRH), also known as luteinizing hormone-releasing hormone, is released by the hypothalamus. It binds to GnRH receptors in the pituitary, increasing the production of follicle-stimulating hormone and luteinizing hormone, thereby stimulating the ovaries to release estrogen. Upon the first use of GnRH analogs, ovarian hormones surge, which can cause side effects such as hot flashes. However, long-term use of GnRH analogs reduces the production and secretion of ovarian hormones, downregulating and decreasing the sensitivity of GnRH receptors in pituitary gonadotropin cells. GnRH receptors are also present in certain cancers, and the reduction of circulating estrogen slows the growth of hormone receptor-positive tumors, such as ovarian cancer, prostate cancer, and breast cancer. Since GnRH analogs have a short half-life, their clinical use is complex. However, by modifying their amino acids, long-acting analogs have been successfully developed and used in the treatment of breast and prostate cancers. Currently used GnRH analogs in clinical settings include goserelin, leuprorelin, and triptorelin.

Somatostatin (AGCKNFFWKTFTSC) is a peptide produced by endocrine cells throughout the gastrointestinal tract that binds to somatostatin receptors (SSTR). Octreotide (FCFWKTCT) is a somatostatin analog that binds to SSTR2 and SSTR5 and acts as an inhibitor of growth hormone, insulin, and glucagon. Octreotide is used to treat severe diarrhea caused by certain intestinal tumors, such as vasoactive intestinal peptide-secreting tumors or metastatic carcinoid tumors.

Table.4 Gonadotropin-releasing hormone (GnRH) related peptides at Creatives Peptides.

Peptide Inhibitors of Intracellular Protein-Protein Interactions

Intracellular protein-protein interactions (PPIs) play a critical role in cells. for example, they facilitate the formation of protein complexes for signal transduction and promote the binding of transcription factors to promoters and enhancers. Therefore, pharmacological methods are used to inhibit intracellular PPIs. related compounds include small molecules with a molecular weight of less than 500 Da and biologics with a molecular weight greater than 5000 Da. Small molecules can effectively pass through cell membranes and regulate the function of intracellular proteins. However, these drugs cannot recognize individual mutations in target sites, and tumor cells can easily develop resistance to these drugs. Additionally, because small molecules are too small, they cannot cover the large surface of proteins involved in protein interactions. In contrast, biologics can bind to larger protein interfaces with high selectivity. However, they have poor cellular permeability. To address the limitations of small molecules and biologics, peptides with molecular weights between 500 and 5000 Da have been developed to interfere with PPIs. These peptides combine the advantages of both small molecules and biologics, including the cell permeability of small molecules and the high selectivity of biologics, covering larger areas of proteins. Since the sequences of peptide inhibitors often come from endogenous proteins involved in interactions, most of them act as natural competitors of protein interactions.

c-Myc is a transcription factor involved in various human malignancies. It typically forms heterodimer complexes with its partner transcription factors, binds to DNA, and regulates gene expression. A 14-amino acid peptide (RQIKIWFQNRRMKWKK) from the Myc helix 1C terminal region can block the interaction between c-Myc and its partner. Another example is OmoMyc, which contains 92 amino acids, derived from the Myc bHLHZip region, but differs from Myc by four amino acid residues.

The Homeobox (HOX) genes are important transcription factors involved in body segmentation and pattern formation during vertebrate development. HOX gene expression is often enhanced in tumors and is related to angiogenesis, metastasis, and proliferation of tumor cells. A common cofactor of HOX is the pre-B-cell leukemia homeobox (PBX). The HXR9 peptide (WYPWMKKHHRRRRRRRRR) interferes with the interaction between HOX and PBX in several mouse tumor models.

KRAS is an oncogenic protein that is often activated in various tumors, including lung cancer and pancreatic cancer. Due to the lack of a classic drug-binding site, it has been considered an untreatable target. The KRpep-2d peptide (Ac-RRRR-cyclo (CPLYISYDPVC)-NH₂) is a cyclic peptide with more than 12 amino acids. The macrocyclic peptides and their derivatives can bind to KRAS and inhibit KRAS downstream signaling and cell proliferation.

Summary

Peptides are of great significance in tumor therapy because they are able to identify tumor cells with high specificity, strong targeting, and few side effects. However, peptide drugs are faced with poor stability, rapid degradation and low bioavailability in clinical applications. By optimizing the pharmacokinetic properties of peptides, such as improving their stability in vivo, enhancing tissue targeting, and prolonging half-life, the efficacy of peptides in tumor therapy can be significantly improved. This not only improves treatment effectiveness, but also reduces damage to normal tissue, making peptides a key tool for developing safer and more effective cancer treatment options.

References

1. Lei, Yu, et al., Peptides as Versatile Regulators in Cancer Immunotherapy: Recent Advances, Challenges, and Future Prospects. Pharmaceutics 17.1 (2025): 46.
2. Yavari, Bahram, et al., The potential use of peptides in cancer treatment. Current Protein and Peptide Science 19.8 (2018): 759-770.