Emerging Combination Therapies Involving Photodynamic Therapy for Basal and Squamous Cell Carcinomas

Calista Persson*; Akhil Gupta

**Calista Persson* and Akhil Gupta**

Volume6-Issue6
Dates: Received: 2025-05-23 | Accepted: 2025-06-15 | Published: 2025-06-16
Pages: 715-728

Abstract

Background: Basal Cell Carcinoma (BCC) and Squamous Cell Carcinoma (SCC) are the most prevalent non-melanoma skin cancers. Photodynamic Therapy (PDT) is an established, non-invasive treatment known for its favorable cosmetic results, especially in superficial lesions. However, its limited penetration restricts effectiveness against thicker or more aggressive tumors, prompting the development of combination strategies to enhance PDT's efficacy.

Methods: This narrative review examines studies published from 2015 to 2025 that explore combining PDT with other treatments for BCC and SCC. A systematic search identified clinical trials, cohort studies, and case reports focusing on combinations with immunotherapy, chemotherapy, physical debulking, nanotechnology, and pharmacologic agents. The analysis considered treatment outcomes, safety, mechanistic insights, and therapeutic synergy.

Results: Combination treatments showed improved tumor clearance rates, reduced recurrence, and enhanced immune responses. Immunomodulators and immune checkpoint inhibitors boosted the immune effects of PDT. Topical chemotherapy, like fluorouracil, enhanced photosensitizer uptake and lesion clearance. Mechanical techniques, such as curettage or laser ablation, improved cure rates for nodular BCC. Nanoparticle delivery systems enabled deeper tissue penetration, while agents like vitamin D analogues and mTOR inhibitors increased tumor sensitivity to PDT. Importantly, these combinations preserved cosmetic outcomes while expanding efficacy for more aggressive lesions.

Conclusion: Integrating PDT with immunological, chemical, physical, or nanotechnological approaches represents a significant advancement in non-melanoma skin cancer treatment. These combinations overcome traditional monotherapy limitations and maintain cosmetic benefits. Future large-scale trials are crucial to refine protocols, validate long-term outcomes, and encourage routine clinical implementation.

FullText HTML FullText PDF DOI: 10.37871/jbres2125

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How to cite this article

Persson C, Gupta A. Emerging Combination Therapies Involving Photodynamic Therapy for Basal and Squamous Cell Carcinomas. J Biomed Res Environ Sci. 2025 Jun 16; 6(6): 715-728. doi: 10.37871/jbres2125, Article ID: JBRES2125, Available at: https://www.jelsciences.com/articles/jbres2125.pdf

Subject area(s)

Oncology

Cancer

Dermatology

References

Peng J, Feng W, Luo X, Wang T, Xiang W, Dai Y, Zhu J, Zheng J. A Clinical Trial Using Attrition Combined with 5-Aminolevulinic Acids Based Photodynamic Therapy in Treating Squamous Cell Carcinoma. Med Sci Monit. 2017 Mar 18;23:1347-1354. doi: 10.12659/msm.900420. PMID: 28314866; PMCID: PMC5367852.
Zhang H, Wang P, Wang X, Shi L, Fan Z, Zhang G, Yang D, Bahavar CF, Zhou F, Chen WR, Wang X. Antitumor Effects of DC Vaccine With ALA-PDT-Induced Immunogenic Apoptotic Cells for Skin Squamous Cell Carcinoma in Mice. Technol Cancer Res Treat. 2018 Jan 1;17:1533033818785275. doi: 10.1177/1533033818785275. PMID: 30025490; PMCID: PMC6053869.
Ferrara F, Lacava R, Barisani A, Messori S, Patrizi A, Bardazzi F, Vaccari S. Combined CO2 laser and photodynamic therapy enhances the efficacy of treatment of basal cell carcinomas. J Dtsch Dermatol Ges. 2019 Dec;17(12):1251-1256. doi: 10.1111/ddg.14004. Epub 2019 Dec 9. PMID: 31814292.
Martins WK, Belotto R, Silva MN, Grasso D, Suriani MD, Lavor TS, Itri R, Baptista MS, Tsubone TM. Autophagy Regulation and Photodynamic Therapy: Insights to Improve Outcomes of Cancer Treatment. Front Oncol. 2021 Jan 20;10:610472. doi: 10.3389/fonc.2020.610472. PMID: 33552982; PMCID: PMC7855851.
Boppana NB, Stochaj U, Kodiha M, Bielawska A, Bielawski J, Pierce JS, Korbelik M, Separovic D. C6-pyridinium ceramide sensitizes SCC17B human head and neck squamous cell carcinoma cells to photodynamic therapy. J Photochem Photobiol B. 2015 Feb;143:163-8. doi: 10.1016/j.jphotobiol.2015.01.001. Epub 2015 Jan 10. PMID: 25635908; PMCID: PMC4662378.
Harris JC, Scully MA, Day ES. Cancer Cell Membrane-Coated Nanoparticles for Cancer Management. Cancers (Basel). 2019 Nov 21;11(12):1836. doi: 10.3390/cancers11121836. PMID: 31766360; PMCID: PMC6966582.
Zeng Q, Yang J, Ji J, Wang P, Zhang L, Yan G, Wu Y, Chen Q, Liu J, Zhang G, Wang X. PD-L1 blockade potentiates the antitumor effects of ALA-PDT and optimizes the tumor microenvironment in cutaneous squamous cell carcinoma. Oncoimmunology. 2022 Apr 3;11(1):2061396. doi: 10.1080/2162402X.2022.2061396. PMID: 35402079; PMCID: PMC8986186.
Ji B, Wei M, Yang B. Recent advances in nanomedicines for photodynamic therapy (PDT)-driven cancer immunotherapy. Theranostics. 2022 Jan 1;12(1):434-458. doi: 10.7150/thno.67300. PMID: 34987658; PMCID: PMC8690913.
Anand S, Shen A, Cheng CE, Chen J, Powers J, Rayman P, Diaz M, Hasan T, Maytin EV. Combination of vitamin D and photodynamic therapy enhances immune responses in murine models of squamous cell skin cancer. Photodiagnosis Photodyn Ther. 2024 Feb;45:103983. doi: 10.1016/j.pdpdt.2024.103983. Epub 2024 Jan 27. PMID: 38281610; PMCID: PMC11197882.
Paolino G, Didona D, Scarnò M, Tallarico M, Cantoresi F, Calvieri S, Mercuri SR, Piccolo D, Bottoni U, Kyriakou A, Cantisani C. Sequential treatment of daylight photodynamic therapy and imiquimod 5% cream for the treatment of superficial basal cell carcinoma on sun exposed areas. Dermatol Ther. 2019 Mar;32(2):e12788. doi: 10.1111/dth.12788. Epub 2018 Dec 21. PMID: 30499211.
Lucena SR, Salazar N, Gracia-Cazaña T, Zamarrón A, González S, Juarranz Á, Gilaberte Y. Combined Treatments with Photodynamic Therapy for Non-Melanoma Skin Cancer. Int J Mol Sci. 2015 Oct 28;16(10):25912-33. doi: 10.3390/ijms161025912. PMID: 26516853; PMCID: PMC4632833.
Liu P, Yang W, Shi L, Zhang H, Xu Y, Wang P, Zhang G, Chen WR, Zhang B, Wang X. Concurrent photothermal therapy and photodynamic therapy for cutaneous squamous cell carcinoma by gold nanoclusters under a single NIR laser irradiation. J Mater Chem B. 2019 Nov 28;7(44):6924-6933. doi: 10.1039/c9tb01573f. Epub 2019 Oct 22. PMID: 31638633.
Yu N, Luo X, Wei T, Zhang Q, Yu J, Wu L, Su J, Chen M, Huang K, Li F, Xie Y, Fang F, Zhang L, He R, Chen X, Zhao S, Bu W. Dermabrasion combined with photodynamic therapy: a new option for the treatment of non-melanoma skin cancer. Lasers Med Sci. 2022 Mar;37(2):1255-1263. doi: 10.1007/s10103-021-03381-3. Epub 2021 Aug 8. PMID: 34365550.
Yang N, Yang Y, Zhang W, Li X, Jiang H, Kou H, Zhang J, Wang Y, Tan L, Lu Y. Efficacy of PDD-guided tumor excision combined with photodynamic therapy in cutaneous squamous cell carcinoma. Photodiagnosis Photodyn Ther. 2025 Feb;51:104469. doi: 10.1016/j.pdpdt.2024.104469. Epub 2025 Jan 1. PMID: 39753196.
Maytin EV, Anand S. Combination photodynamic therapy using 5-fluorouracil and aminolevulinate enhances tumor-selective production of protoporphyrin IX and improves treatment efficacy of squamous skin cancers and precancers. Proc SPIE. 2016. doi: 10.1117/12.2218138.
Anand S, Hasan T, Maytin EV. Treatment of nonmelanoma skin cancer with pro-differentiation agents and photodynamic therapy: Preclinical and clinical studies (Review). Photochem Photobiol. 2024 Nov-Dec;100(6):1541-1560. doi: 10.1111/php.13914. Epub 2024 Feb 4. PMID: 38310633; PMCID: PMC11297983.
Yu N, Luo X, Wei T, Zhang Q, Yu J, Wu L, Su J, Chen M, Huang K, Li F, Xie Y, Fang F, Zhang L, He R, Chen X, Zhao S, Bu W. Dermabrasion combined with photodynamic therapy: a new option for the treatment of non-melanoma skin cancer. Lasers Med Sci. 2022 Mar;37(2):1255-1263. doi: 10.1007/s10103-021-03381-3. Epub 2021 Aug 8. PMID: 34365550.
Collier NJ, Rhodes LE. Photodynamic Therapy for Basal Cell Carcinoma: The Clinical Context for Future Research Priorities. Molecules. 2020 Nov 18;25(22):5398. doi: 10.3390/molecules25225398. PMID: 33218174; PMCID: PMC7698957.
Zhang M, Zhao Y, Ma H, Sun Y, Cao J. How to improve photodynamic therapy-induced antitumor immunity for cancer treatment? Theranostics. 2022 May 29;12(10):4629-4655. doi: 10.7150/thno.72465. PMID: 35832074; PMCID: PMC9254244.
Valerio TI, Furrer CL, Sadeghipour N, Patrock SX, Tillery SA, Hoover AR, Liu K, Chen WR. Immune modulations of the tumor microenvironment in response to phototherapy. J Innov Opt Health Sci. 2023 May;16(3):2330007. doi: 10.1142/s1793545823300070. Epub 2023 Apr 27. PMID: 38550850; PMCID: PMC10976517.
Adnane F, El-Zayat E, Fahmy HM. The combinational application of photodynamic therapy and nanotechnology in skin cancer treatment: A review. Tissue Cell. 2022 Aug;77:101856. doi: 10.1016/j.tice.2022.101856. Epub 2022 Jun 15. PMID: 35759978.
Chen Y, Zhi S, Ou J, Gao J, Zheng L, Huang M, Du S, Shi L, Tu Y, Cheng K. Cancer Cell Membrane-Coated Nanoparticle Co-loaded with Photosensitizer and Toll-like Receptor 7 Agonist for the Enhancement of Combined Tumor Immunotherapy. ACS Nano. 2023 Sep 12;17(17):16620-16632. doi: 10.1021/acsnano.3c02724. Epub 2023 Aug 22. PMID: 37606341.
Nicolás-Morala J, Mascaraque-Checa M, Gallego-Rentero M, Barahona A, Abarca-Lachen E, Carrasco E, Gilaberte Y, González S, Juarranz Á. The m-TORC1 inhibitor Sirolimus increases the effectiveness of Photodynamic therapy in the treatment of cutaneous Squamous Cell Carcinoma, impairing NRF2 antioxidant signaling. Int J Biol Sci. 2024 Aug 6;20(11):4238-4257. doi: 10.7150/ijbs.94883. PMID: 39247827; PMCID: PMC11379070.
Alma A, Pongetti L, Clementi A, Chester J, Toccaceli M, Ciardo S, Zappia E, Manfredini M, Pellacani G, Greco M, Bennardo L, Farnetani F. Combined Carbon Dioxide Laser with Photodynamic Therapy for Nodular Basal Cell Carcinoma Monitored by Reflectance Confocal Microscopy. Medicina (Kaunas). 2023 Dec 24;60(1):30. doi: 10.3390/medicina60010030. PMID: 38256291; PMCID: PMC10821002.
Xu M, Kong L, Jamil M. Advancements in skin cancer treatment: focus on photodynamic therapy: a review. Am J Cancer Res. 2024 Oct 25;14(10):5011-5044. doi: 10.62347/JOUT3260. PMID: 39553219; PMCID: PMC11560809.
Zeng L, Gowda BHJ, Ahmed MG, Abourehab MAS, Chen ZS, Zhang C, Li J, Kesharwani P. Advancements in nanoparticle-based treatment approaches for skin cancer therapy. Mol Cancer. 2023 Jan 12;22(1):10. doi: 10.1186/s12943-022-01708-4. PMID: 36635761; PMCID: PMC9835394.
Lultschik S, Tran J, Sapra S, Sharma K, Dong K. Non-Invasive Treatment of Basal Cell Carcinoma: Photodynamic Therapy Following Curettage. J Drugs Dermatol. 2023 May 1;22(5):481-485. doi: 10.36849/JDD.7133. PMID: 37133481.
Zeng Q, Yang J, Ji J, Wang P, Zhang L, Yan G, Wu Y, Chen Q, Liu J, Zhang G, Wang X. PD-L1 blockade potentiates the antitumor effects of ALA-PDT and optimizes the tumor microenvironment in cutaneous squamous cell carcinoma. Oncoimmunology. 2022 Apr 3;11(1):2061396. doi: 10.1080/2162402X.2022.2061396. PMID: 35402079; PMCID: PMC8986186.
Champeau M, Vignoud S, Mortier L, Mordon S. Photodynamic therapy for skin cancer: How to enhance drug penetration? J Photochem Photobiol B. 2019 Aug;197:111544. doi: 10.1016/j.jphotobiol.2019.111544. Epub 2019 Jul 2. PMID: 31295716.
Tian D, Teng C, Lv Y, Duan X, Wang Y, Song X, Jiang Q, Huang D, Xin T, Yang Y, Li L. Photodynamic therapy with intratumoral injection of photosensitizers combined with immunotherapy brings hope to patients with refractory cutaneous malignant ulcers. Discov Oncol. 2024 Oct 4;15(1):522. doi: 10.1007/s12672-024-01342-0. PMID: 39365490; PMCID: PMC11452570.
Kobauri P, Dekker FJ, Szymanski W, Feringa BL. Rational design in photopharmacology with molecular photoswitches. Angew Chem Int Ed Engl. 2023;62(30):e202300681. doi: 10.1002/anie.202300681.
Baioco KS, Pereira R, Ferreira-Gonçalves T, Coelho JMP, Gaspar MM, Reis CP. Combining Phototherapy and Gold-Based Nanomaterials: A Breakthrough in Basal Cell Carcinoma Treatment. Int J Mol Sci. 2024 Oct 26;25(21):11494. doi: 10.3390/ijms252111494. PMID: 39519051; PMCID: PMC11545837.
Rollakanti K, Anand S, Maytin EV. Topical calcitriol prior to photodynamic therapy enhances treatment efficacy in non-melanoma skin cancer mouse models. Proc SPIE Int Soc Opt Eng. 2015 Mar 2;9308:93080Q. doi: 10.1117/12.2077296. PMID: 25983370; PMCID: PMC4429796.