2025 marks a period of intensive breakthroughs in the development of tumor peptide drugs. From cyclic peptides targeting "undruggable" targets to short peptides with dual functions of immunomodulation and photodynamic therapy, and then to the LYTAC peptide system that degrades cell membrane proteins, a series of advancements are reshaping the role of "peptide drugs" in cancer treatment-they are no longer cheap substitutes for antibodies, but are becoming an independent and logically consistent therapeutic toolbox.
I. Cyclic Peptides: Breaking Through the "Undruggable" Barrier
Cyclic peptides are becoming the most watched molecular type in the field of protein-protein interaction (PPI) targeting. Compared with traditional linear peptides, cyclic structures endow them with stronger metabolic stability, higher target affinity, and better membrane permeability.
Paluratide (LUNA18) is a representative molecule of this trend. This cyclic peptide, developed by Chunghwa Pharmaceutical, directly targets the RAS-SOS1 interaction, and RAS has long been considered a benchmark for "undruggable" targets. LUNA18 is currently in a Phase I clinical trial (NCT05012618) being evaluated as an oral monotherapy and in combination with cetuximab.
In the glioblastoma field, VT1021 (a 638.76 Da cyclic peptide) targets the CD36/CD47 immune checkpoint axis and is currently being evaluated in a Phase III trial (NCT03970447). This molecule can cross the blood-brain barrier and modulate the immunosuppressive microenvironment specific to glioblastoma, addressing the urgent need for new therapies in this field.
Zelenectide pevedotin (BT8009) represents another direction in the evolution of cyclic peptide technology-bicyclic peptide-drug conjugates. This molecule targets Nectin-4 expressing tumors, and its efficacy in urothelial carcinoma is currently being evaluated in a Phase III trial (NCT06225596). The bicyclic peptide structure retains the targeting advantages of cyclic peptides while providing a more rigid conformation, which is beneficial for optimizing pharmacokinetic properties.
II. PDCs: A New Platform for Precision Drug Killing
Peptide-drug conjugates (PDCs) are playing an increasingly important role in targeted cancer therapy. Compared to ADCs, PDCs have smaller molecular weights (typically 2-10 kDa vs. ~150 kDa for ADCs), resulting in better tumor penetration and lower immunogenicity risk.
In the field of triple-negative breast cancer (TNBC), researchers have developed a class of cyclic peptide PDCs targeting TROP2. TROP2 is a transmembrane glycoprotein overexpressed in various epithelial malignancies and is associated with tumor invasiveness and poor prognosis. TROP2-binding cyclic peptides obtained through phage display screening, after alanine scanning optimization, were conjugated with pro-apoptotic peptides or MMAEs, achieving cytotoxicity with an IC50 of 25.6 nM in TROP2-high expressing TNBC cells, while exhibiting almost no toxicity in TROP2-low expressing or normal cells.
In another study, researchers constructed a reduction-responsive PDC (RGDC-SS-DTX) by linking an RGD-targeting peptide with docetaxel (DTX) via a disulfide bond. This design leverages the high concentration of glutathione (GSH) within tumor cells: disulfide bonds are efficiently reduced within tumor cells, releasing the active drug, while remaining stable in normal cells. In vitro studies have shown that RGDC-SS-DTX is superior to free DTX in G2/M phase arrest and apoptosis induction in tumor cells, while significantly reducing toxicity to normal cells. This strategy demonstrates how the PDC platform can achieve spatially precise drug delivery through responsive linker design.
III. PD-L1 Targeting Peptide: When Immune Checkpoint Inhibitors are "Miniaturized"
Antibody-based immune checkpoint inhibitors (ICIs) face challenges such as high cost, poor tumor penetration, and systemic toxicity. Peptide-based ICIs offer a potential alternative, but most suffer from insufficient in vivo efficacy.
IKCRPCY (IKC)-a heptapeptide identified through phage display-offers a different answer. This peptide exhibits nanomolar affinity for PD-L1 and can restore IL-2 secretion in co-cultured T cells. Researchers further designed a conjugate of Ce6 with dihydroporphyrin e6 (Ce6) (Ce6-IKC), achieving a synergistic effect of photodynamic therapy and immune checkpoint blockade.
In the CT26 bilateral tumor model, Ce6-IKC PDT combined with IKC treatment significantly inhibited tumor growth, induced the expression of immunogenic cell death markers (Calreticulin, HMGB1), and increased CD8+ T cell infiltration. More importantly, the contralateral (untreated) tumor burden was reduced by 72%-clear evidence of the abscopal effect.
This work illustrates a unique advantage of peptide drugs: they can integrate multiple therapeutic functions into a single molecule through chemical modification, which is far more complex to achieve in antibody platforms.
IV. Peptide LYTACs: A New Paradigm for Extracellular Target Degradation Targeted protein degradation (TPD) technologies-including PROTACs and molecular glues-have revolutionized the design logic of small molecule drugs. However, these technologies can only degrade intracellular proteins. Cell membrane proteins and secreted proteins (accounting for approximately 40% of human coding genes) remain outside its reach.
The LYTAC (lysosomal targeted chimera) concept proposed by Bertozzi's team in 2020 filled this gap. Antibody-based LYTACs suffer from cumbersome synthesis, limited tumor penetration, and high cost.
Researchers turned to the GLP-1-based peptide LYTAC system (APCTAC). This system couples GLP-1 analogs (such as modified sequences of smegglutinin or exenatide) to target protein binding molecules, guiding target proteins (such as PD-L1) on the cell surface into lysosomes for degradation.
In animal models, APCTAC achieved potent degradation of PD-L1, transforming the immunosuppressive tumor microenvironment into an immunostimulatory microenvironment. Compared to antibody therapy, APCTAC achieved comparable or superior anti-tumor efficacy while inducing significantly less inflammatory damage.
This points to a direction: peptide drugs are shifting from "targeting" to "degradation," and from "inhibitory signals" to "eliminating molecules." V. Innovative Delivery: Overcoming the Blood-Brain Barrier and Improving Pharmacokinetics
A long-standing problem with peptide drugs is their poor in vivo stability and short half-life. Current research is addressing this challenge from various angles.
In glioblastoma treatment, researchers have developed self-assembled peptide-drug conjugates (OncoPDCs) that bypass the blood-brain barrier and are directly injected into the brain parenchyma via convection-enhanced delivery (CED). These conjugates contain three functional modules: a receptor-binding ligand (targeting IL4Rα or IL13Rα2), an intrinsically disordered peptide domain (achieving sustained release in the brain), and an anti-tumor drug (SN38). The self-assembled structure forms an in-situ reservoir triggered by body temperature, prolonging the drug's residence time at the tumor site and providing a new strategy for addressing the challenge of rapid clearance of gliomas after surgery.
In terms of systemic delivery, pH-responsive polymer nanoparticles are used for targeted delivery of anti-PD-L1 peptides and synergistic activation of the STING pathway. This nanosystem, self-assembled from a PEO-PC7A amphiphilic block copolymer, remains stable at neutral pH and releases an anti-PD-L1 peptide in the acidic tumor microenvironment (pH 6.2-6.8). Simultaneously, the PC7A domain itself can activate the cGAS-STING pathway, achieving integrated immune checkpoint blockade and innate immune activation. This "single-material, dual-function" strategy represents a new direction in nanodelivery system design.
Conclusion: From "Carrier" to "Therapeutic Logic"
In the past, the role of peptides in tumor research was often simplified to "targeting ligands"-a navigator that delivers drugs to their destination. However, the aforementioned progress reveals a completely different picture:
Peptides are becoming the core of therapeutic logic.
These can be cyclic peptide molecules that directly block undrugable PPI targets like RAS-SOS1; they can be "recognition modules + response switches" in PDCs, such as RGDC-SS-DTX, which releases the drug in response to a reducing environment within tumor cells; they can be "bifunctional molecules" that integrate immune checkpoint blockade and photodynamic therapy through chemical modification; they can be LYTAC systems that eliminate PD-L1 through degradation rather than inhibition; or they can be intelligent systems combined with nanodelivery platforms, simultaneously playing a role in pharmacokinetic optimization and immune activation.
The real novelty lies not in "yet another peptide drug," but in the fact that peptides are transcending their role as "backup" drugs for antibodies, developing a logically consistent intervention paradigm that is entirely different from antibodies and small molecules. Their unique combination of molecular size, targeting methods, mechanisms of action, and programmability is giving them irreplaceable value in certain dimensions of cancer treatment-especially in targeting PPIs, precise degradation, and multifunctional molecular design.