• N. KHRANOVSKA Nonprofit organization “National Cancer Institute”, Kyiv, Ukraine
  • O. SKACHKOVA Nonprofit organization “National Cancer Institute”, Kyiv, Ukraine
  • O. GORBACH Nonprofit organization “National Cancer Institute”, Kyiv, Ukraine
  • I. SEMCHUK Nonprofit organization “National Cancer Institute”, Kyiv, Ukraine
  • Yu. SHVETS Taras Shevchenko National University of Kyiv, Kyiv, Ukraine
  • I. KOMAROV Taras Shevchenko National University of Kyiv, Kyiv, Ukraine



oncolytic peptides, immunogenic cell death, anticancer immunity, molecular photoswitch


Oncolytic peptides are derived from natural host defense peptides/antimicrobial peptides produced in a wide variety of life forms. Over the past two decades, they have attracted much attention in both basic research and clinical applications. Oncolytic peptides were expected to act primarily on tumor cells and also trigger the immunogenic cell death. Their ability in the tumor microenvironment remodeling and potentiating the anticancer immunity has long been ignored. Despite the promising results, clinical application of oncolytic peptides is still hindered by their unsatisfactory bioactivity and toxicity to normal cells. To ensure safer therapy, various approaches are being developed. The idea of the Ukrainian research group was to equip peptide molecules with a "molecular photoswitch" — a diarylethene fragment capable of photoisomerization, allowing for the localized photoactivation of peptides within tumors reducing side effects. Such oncolytic peptides that may induce the membrane lysis-mediated cancer cell death and subsequent anticancer immune responses in combination with the low toxicity to normal cells have provided a new paradigm for cancer therapy. This review gives an overview of the broad effects and perspectives of oncolytic peptides in anticancer immunity highlighting the potential issues related to the use of oncolytic peptides in cancer immunotherapy. We summarize the current status of research on peptide-based tumor immunotherapy in combination with other therapies including immune checkpoint inhibitors, chemotherapy, and targeted therapy.


Tang T, Huang X, Zhang G, Liang T. Oncolytic immunotherapy: multiple mechanisms of oncolytic peptides to confer anticancer immunity. J Immunother Cancer. 2022;10:e005065.

Newman DJ. Cragg MG. Natural products as sources of new drugs over the nearly four decades from 01/1981 to 09/2019. J Nat Prod. 2020;83:770-803. /acs.jnatprod.9b01285

Zhang Y, Liu C, Wu C, Song L. Natural peptides for immunological regulation in cancer therapy:

Mechanism, facts and perspectives. Biomed Pharmacother. 2023;159:114257.

Liu H, Shen W, Liu W, et al. From oncolytic peptides to oncolytic polymers: A new paradigm for oncotherapy. Bioact Mater. 2024;31:206-230.

Ványolós A, Dékány M, Kovács B, et al. Gymnopeptides A and B, cyclic octadecapeptides from the mushroom Gymnopus fusipes. Org Lett. 2016;18(11):2688.

Lee J, Curanno JN, Carroll PJ, et al. Didemnins, tamandarins and related natural products. Nat Prod Rep. 2012;29(3):404-424.

Boudreau PD, Byrum T, Liu WT, et al. Viequeamide A, a cytotoxic member of the kulolide superfamily of cyclic depsipeptides from a marine button cyanobacterium. J Nat Prod. 2012;75(9):1560-1570.

Zasloff M. Antimicrobial peptides of multicellular organisms. Nature. 2002;415:389–395.

Camilio KA, Berge G, Ravuri CS, et al. Complete regression and systemic protective immune responses obtained in B16 melanomas after treatment with LTX-315. Cancer Immunol Immunother. 2014;63(6):601-613.

Chen CH, Lu TK. Development and challenges of antimicrobial peptides for therapeutic applications. Antibiotics. 2020;9:24.

Xie M, Liu D, Yang Y. Anti-cancer peptides: classification, mechanism of action, reconstruction and modification. Open Biol. 2020;10:200004.

Eike LM, Yang N, Rekdal O, et al. The oncolytic peptide LTX-315 induces cell death and DAMP release by mitochondria distortion in human melanoma cells. Oncotarget. 2015;6:34910-34923.

Zhou H, Forveille S, Sauvat A, et al. The oncolytic peptide LTX-315 triggers immunogenic cell death. Cell Death Dis. 2016;7:e2134.

Yamazaki T, Pitt JM, Vétizou M, et al. The oncolytic peptide LTX-315 overcomes resistance of cancers to immunotherapy with CTLA4 checkpoint blockade. Cell Death Differ. 2016;1:12.

Haug BE, Camilio KA, Eliassen LT, et al. Discovery of a 9-mer cationic peptide (LTX-315) as a potential first in class oncolytic peptide. J Med Chem. 2016;59:2918-2927.

Furukawa N, Yang W, Chao A, et al. Chemokine-derived oncolytic peptide induces immunogenic cancer cell death and significantly suppresses tumor growth. Res Sq. 2023;

O'Connell KM, Hodgkinson JT, Sore HF, et al. Combating multidrug-resistant bacteria: current strategies for the discovery of novel antibacterials. Angew Chem Int Ed Engl. 2013;4;52(41):10706-10733.

David JM, Rajasekaran AK. Gramicidin A: a new mission for an old antibiotic. J Kidney Cancer VHL. 2015;2(1):15-24.

Mogi T, Kita K. Gramicidin S and polymyxins: the revival of cationic cyclic peptide antibiotics. Cell Mol Life Sci. 2009;66:3821-3826.

Galluzzi L, Humeau J, Buqué A, et al. (2020). Immunostimulation with chemotherapy in the era of immune checkpoint inhibitors. Nat Rev Clin Oncol. 2020;17(12):725-741.

Sveinbjørnsson B, Camilio KA, Haug BE, et al. LTX-315: a first-in-class oncolytic peptide that reprograms the tumor microenvironment. Future Med Chem. 2017;9(12):1339-1344.

Li XQ, Yamazaki T, He T, LTX-315 triggers anticancer immunity by inducing MyD88-dependent maturation of dendritic cells. Front Immunol. 2024;15:1332922.

Zhou J, Wang G, Chen Y, et al. Immunogenic cell death in cancer therapy: present and emerging inducers. J Cell Mol Med. 2019;23(8):4854.

Tornesello AL, Borrelli A, Buonaguro L, et al. Antimicrobial peptides as anticancer agents: functional properties and biological activities. Molecules 2020;25:2850.

Berge G, Eliassen LT, Camilio KA, et al. Therapeutic vaccination against a murine lymphoma by intratumoral injection of a cationic anticancer peptide. Cancer Immunol Immunother. 2010;59:1285-1294.

Ji SY, Lee H, Hwangbo H, et al. A novel peptide oligomer of bacitracin induces M1 macrophage polarization by facilitating Ca2+ influx. Nutrients. 2020;12:1603.

Yang B, Good D, Mosaiab T, et al. Significance of LL-37 on immunomodulation and disease outcome. BioMed Res Int. 2020;2020:8349712.

Li Y, Bionda N, Yongye A, et al. Dissociation of antimicrobial and hemolytic activities of gramicidin S through N-methylation modification. ChemMedChem. 2013;8(11):1865-1872.

Moual HL, Thomassin J-L, Brannon JR. Antimicrobial peptides as an alternative approach to treat bacterial infections. J Clin Cell Immunol. 2013:S13.

Tripathi AK, Vishwanatha JK. Role of anti-cancer peptides as immunomodulatory agents: potential and design strategy. Pharmaceutics. 2022;14(12):2686.

He S, Deber CM. Interaction of designed cationic antimicrobial peptides with the outer membrane of gram-negative bacteria. Sci Rep. 2024;14:1894.

Hadianamrei R, Tomeh MA, Brown S, et al. Rationally designed short cationic alpha-helical peptides with selective anticancer activity. J Colloid Interface Sci. 2022;607:488-501.

Wang L, Wang N, Zhang W, et al. Therapeutic peptides: current applications and future directions. Signal Transduct Target Ther. 2022;7(1):48.

Babii O, Afonin S, Schober T, et al. Peptide drugs for photopharmacology: how much of a safety advantage can be gained by photocontrol? Future Drug Discovery. 2020;2(6):1-14.

Komarov IV, Tolstanova G, Kuznietsova H, et al. Towards in vivo photomediated delivery of anticancer peptides: Insights from pharmacokinetic and-dynamic data. J Photochem Photobiol B. 2022;233:112479.

Dougherty TJ, Kaufman JE, Goldfarb A, et al. Photoradiation therapy for the treatment of malignant tumors. Cancer Res. 1978;38:2628-2635. PMID: 667856

Wilson BC, Patterson MS. The physics, biophysics and technology of photodynamic therapy. Phys Med Biol. 2008;53(9): R61-R109.

Lerch, MM, Hansen, MJ, van Dam, GM, et al. Emerging targets in photopharmacology. Angew Chem Int Ed. 2016;55:10978-10999.

Schoenberger M, Damijonaitis A, Zhang Z, et al. Development of a new photochromic ion channel blocker via azologization of fomocaine. ACS Chem. Neurosci. 2014;5(7):514-518.

Borowiak M, Nahaboo W, Reynders M, et al. Photoswitchable inhibitors of microtubule dynamics optically control mitosis and cell death. Cell. 2015;162(2):403-411.

Afonin S, Babii O, Komarov I, et al.; Karlsruher Institut fur Technologie. Peptidomimetics possessing photocontrolled biological activity. US patent 9.481,712 B2. November 1. 2016.

Babii O, Afonin S, Berditschet M, et al. Controlling biological activity with light: diarylethene-containing cyclic peptidomimetics. Angew Chem Int Ed. 2014;53:3392-3395.

Wipf Р, Skoda EM, Mann. The practice of medicinal chemistry (Fourth Edition). Conformational Restriction and Steric Hindrance in Medicinal Chemistry. 2015;11:279-299.

Afonin S, Babii O, Reuter A, et al. Light-controllable dithienylethene-modified cyclic peptides: Photoswitching the in vivo toxicity in zebrafish embryos. Beilstein J Org Chem. 2020;16:39-49.

Horbatok K, Makhnii T, Kosach V, et al. In vitro and in vivo evaluation of photocontrolled biologically active compounds - potential drug candidates for cancer photopharmacology. J. Vis Exp. 2023;199:e64902.

Komarov IV, Tolstanova G, Kuznietsova H. Towards in vivo photomediated delivery of anticancer peptides: Insights from pharmacokinetic and -dynamic data. J Photochem Photobiol. 2022; 233.

Spice JF, Marabelle A, Baurain J-F, A phase I/II study of the oncolytic peptide LTX-315 combined with checkpoint inhibition generates de novo T-cell responses and clinical benefit in patients with advanced solid tumors. J Clin Oncol. 2018;36(15_suppl):3094-3094.

Camilio KA, Wang MYu, Mauseth B, et al. Combining the oncolytic peptide LTX-315 with doxorubicin demonstrates therapeutic potential in a triple-negative breast cancer model. Breast Cancer Res. 2019;21(1):9.

Jin H, Zhao G, Hu J, et al. Melittin-containing hybrid peptide hydrogels for enhanced photothermal therapy of glioblastoma. ACS Appl Mater Interfaces. 2017;9(31):25755-25766.

Lu S, Zhao F, Zhang Q, Chen P. Therapeutic peptide amphiphile as a drug carrier with ATP-triggered release for synergistic effect, improved therapeutic index, and penetration of 3D cancer cell spheroids. Int J Mol Sci. 2018;19(9):2773.

Li J, Zhang P, Zhou M, et al. Trauma-responsive scaffold synchronizing oncolysis immunization and inflammation alleviation for post-operative suppression of cancer metastasis. ACS Nano. 2022;16:6064-6079.

Bonaventura P, Shekarian T, Alcazer V, at al. Cold tumors: a therapeutic challenge for immunotherapy. Front Immunol. 2019;10:168.

Marabelle A, Baurainet JF, Awada A, et al. A Phase I study of the oncolytic peptide LTX-315 generates de novo T-cell responses and clinical benefit in patients with advanced melanoma. Cancer Res. 2019;79(13_Suppl):CT069.




How to Cite