Overcoming three-layered tumor microenvironmental barriers to photodynamic therapy-induced systemic antitumor immunity

Yuqing Pan; Xiangdong Xue

doi:10.70401/bmeh.2026.0032

Overcoming three-layered tumor microenvironmental barriers to photodynamic therapy-induced systemic antitumor immunity

Yuqing Pan

Xiangdong Xue

*Correspondence to: Xiangdong Xue, Shanghai Frontiers Science Center of Drug Target Identification and Delivery, National Key Laboratory of Innovative Immunotherapy, School of Pharmaceutical Sciences, Shanghai Jiao Tong University, Shanghai 200240, China. E-mail: xuexd@sjtu.edu.cn

BME Horiz. 2026;4:202624. 10.70401/bmeh.2026.0032

Received: June 10, 2026Accepted: July 30, 2026Published: July 31, 2026

This article belongs to the Special lssue Nanomaterials for Advanced Molecular Imaging in Oncology

This manuscript is made available in its unedited form to allow early access to the reported findings. Further editing will be completed before final publication. As such, the content may include errors, and standard legal disclaimers are applicable.

Abstract

Photodynamic therapy (PDT) induces immunogenic cell death (ICD) through reactive oxygen species (ROS) generation, bridging localized tumor ablation with systemic antitumor immunity. However, the tumor microenvironment (TME) erects three barriers that intercept the PDT-immune cascade at distinct levels. The biochemical barrier, defined by chronic hypoxia and elevated antioxidant defenses, restricts ROS accumulation below the ICD threshold. The physical barrier, constructed by dense extracellular matrix and activated cancer-associated fibroblasts, confines photosensitizers to the tumor periphery and excludes effector immune cells. The immunosuppressive barrier, mediated by tumor-associated macrophages, regulatory T cells, and myeloid-derived suppressor cells, neutralizes immune activation signals even after successful ICD induction. These barriers are deeply coupled: breaching any single layer yields limited benefit when the others remain intact. This review examines how barrier-oriented PDT-immunotherapy strategies, particularly nanoplatform-enabled approaches, can relieve these three barriers and restore the PDT-immune cascade.

Keywords

Photodynamic therapy, tumor microenvironment barriers, immunogenic cell death, immunotherapy, nanoplatform

References

1. Agostinis P, Berg K, Cengel KA, Foster TH, Girotti AW, Gollnick SO, et al. Photodynamic therapy of cancer: An update. CA Cancer J Clin. 2011;61(4):250-281.

[DOI] [PubMed] [PMC]
2. Castano AP, Mroz P, Hamblin MR. Photodynamic therapy and anti-tumour immunity. Nat Rev Cancer. 2006;6(7):535-545.

[DOI] [PubMed] [PMC]
3. Li X, Lovell JF, Yoon J, Chen X. Clinical development and potential of photothermal and photodynamic therapies for cancer. Nat Rev Clin Oncol. 2020;17(11):657-674.

[DOI] [PubMed]
4. Kroemer G, Galassi C, Zitvogel L, Galluzzi L. Immunogenic cell stress and death. Nat Immunol. 2022;23(4):487-500.

[DOI]
5. De Visser KE, Joyce JA. The evolving tumor microenvironment: From cancer initiation to metastatic outgrowth. Cancer Cell. 2023;41(3):374-403.

[DOI] [PubMed]
6. Singleton DC, Macann A, Wilson WR. Therapeutic targeting of the hypoxic tumour microenvironment. Nat Rev Clin Oncol. 2021;18(12):751-772.

[DOI] [PubMed]
7. Mao X, Xu J, Wang W, Liang C, Hua J, Liu J, et al. Crosstalk between cancer-associated fibroblasts and immune cells in the tumor microenvironment: New findings and future perspectives. Mol Cancer. 2021;20(1):131.

[DOI] [PubMed] [PMC]
8. Bejarano L, Jordāo MJC, Joyce JA. Therapeutic targeting of the tumor microenvironment. Cancer Discov. 2021;11(4):933-959.

[DOI]
9. Morad G, Helmink BA, Sharma P, Wargo JA. Hallmarks of response, resistance, and toxicity to immune checkpoint blockade. Cell. 2021;184(21):5309-5337.

[DOI] [PubMed] [PMC]
10. Mitchell MJ, Billingsley MM, Haley RM, Wechsler ME, Peppas NA, Langer R. Engineering precision nanoparticles for drug delivery. Nat Rev Drug Discov. 2021;20(2):101-124.

[DOI]
11. Cheng Z, Li M, Dey R, Chen Y. Nanomaterials for cancer therapy: Current progress and perspectives. J Hematol Oncol. 2021;14(1):85.

[DOI] [PubMed] [PMC]
12. Ding Q, Qi M, Li W, Li M, Xu J, Kim Y, et al. Precision phototherapy enabled by decoding complex microenvironments. Acc Chem Res. 2025;58(20):3167-3183.

[DOI] [PubMed]
13. Wilson WR, Hay MP. Targeting hypoxia in cancer therapy. Nat Rev Cancer. 2011;11(6):393-410.

[DOI] [PubMed]
14. Lucky SS, Soo KC, Zhang Y. Nanoparticles in photodynamic therapy. Chem Rev. 2015;115(4):1990-2042.

[DOI] [PubMed]
15. Tang Z, Shu J, Luo AL, Wu X, Feng T, Chao H. Oxygen self-sufficient Ir-Mn^II/III coordination-assembled nanoparticles evoke apoptosis and ferroptosis for boosting hypoxic melanoma photoimmunotherapy. ACS Nano. 2026;20(6):5271-5287.

[DOI] [PubMed]
16. Qu H, Chen H, Cheng W, Pan Y, Duan Z, Wang Y, et al. Charge-reversible crosslinked nanoparticle for pro-apoptotic peptide delivery and synergistic photodynamic cancer therapy. Nano Res. 2023;16(12):13267-13282.

[DOI]
17. Li J, Pang E, Debnath S, Hong J, Qiu A, Kim D, et al. Self-immolative activatable nanoassembly toward immuno-photodynamic therapy in TME. Adv Funct Mater. 2026;36(14):e13250.

[DOI]
18. Huang X, Wang L, Guan Q, Chen L, Qi H, Wang H, et al. Self-amplifying nanomedicine reprograms redox metabolism to trigger immunogenic ferroptosis in colon cancer: Multiomics identifies AMPD3 as a novel regulator. Biomaterials. 2026;333:124196.

[DOI]
19. Tang N, Tong F, Wu P, Xie X, Wang L, Yu M, et al. Glutathione/cysteine dual-consuming prodrug nanoassemblies for potentiated gas-photodynamic therapy. Adv Funct Mater. 2025;35(37):2503604.

[DOI]
20. Zou J, Jiang C, Hu Q, Jia X, Wang S, Wan S, et al. Tumor microenvironment-responsive engineered hybrid nanomedicine for photodynamic-immunotherapy via multi-pronged amplification of reactive oxygen species. Nat Commun. 2025;16(1):424.

[DOI] [PubMed] [PMC]
21. Xu S, Xie X, He P, Zhu S, Li X, Chen Q, et al. Nitric oxide-producing multiple functional nanoparticle remodeling tumor microenvironment for synergistic photodynamic immunotherapy against hypoxic tumor. ACS Nano. 2025;19(6):6371-6387.

[DOI] [PubMed]
22. Sahai E, Astsaturov I, Cukierman E, DeNardo DG, Egeblad M, Evans RM, et al. A framework for advancing our understanding of cancer-associated fibroblasts. Nat Rev Cancer. 2020;20(3):174-186.

[DOI] [PubMed] [PMC]
23. Kalluri R. The biology and function of fibroblasts in cancer. Nat Rev Cancer. 2016;16(9):582-598.

[DOI] [PubMed]
24. Izci M, Maksoudian C, Manshian BB, Soenen SJ. The use of alternative strategies for enhanced nanoparticle delivery to solid tumors. Chem Rev. 2021;121(3):1746-1803.

[DOI] [PubMed] [PMC]
25. Overchuk M, Weersink RA, Wilson BC, Zheng G. Photodynamic and photothermal therapies: Synergy opportunities for nanomedicine. ACS Nano. 2023;17(9):7979-8003.

[DOI] [PubMed] [PMC]
26. Yang C, McAndrews KM, Kalluri R. Clinical and therapeutic relevance of cancer-associated fibroblasts. Nat Rev Clin Oncol. 2021;18(12):792-804.

[DOI]
27. Sun Q, Li Y, Shen W, Shang W, Xu Y, Yang J, et al. Breaking-down tumoral physical barrier by remotely unwrapping metal-polyphenol-packaged hyaluronidase for optimizing photothermal/photodynamic therapy-induced immune response. Adv Mater. 2024;36(18):e2310673.

[DOI] [PubMed]
28. Zhao R, Hou Y, Li B, Pan Z, Qiu J, Wang Q, et al. Bioengineered hybrid dual-targeting nanoparticles reprogram the tumour microenvironment for deep glioblastoma photodynamic therapy. Nat Commun. 2025;16(1):7672.

[DOI] [PubMed] [PMC]
29. Cheng W, Qu H, Yang J, Chen H, Pan Y, Duan Z, et al. Hierarchically engineered self-adaptive nanoplatform guided intuitive and precision interventions for deep-seated glioblastoma. ACS Nano. 2025;19(1):557-579.

[DOI] [PubMed]
30. Xue X, Huang Y, Bo R, Jia B, Wu H, Yuan Y, et al. Trojan Horse nanotheranostics with dual transformability and multifunctionality for highly effective cancer treatment. Nat Commun. 2018;9(1):3653.

[DOI] [PubMed] [PMC]
31. Wu Y, Jia W, Xia T, Liao J, He W, Wang H, et al. NIR-actuated morphodynamic 2D nanopatches for interface-programmed immunoactivation and tumor regression. J Am Chem Soc. 2026;148(3):2902-2919.

[DOI] [PubMed]
32. He L, Yu X, Li W. Recent progress and trends in X-ray-induced photodynamic therapy with low radiation doses. ACS Nano. 2022;16(12):19691-19721.

[DOI] [PubMed]
33. Wang X, Sun W, Shi H, Ma H, Niu G, Li Y, et al. Organic phosphorescent nanoscintillator for low-dose X-ray-induced photodynamic therapy. Nat Commun. 2022;13(1):5091.

[DOI] [PubMed] [PMC]
34. Ni D, Ferreira CA, Barnhart TE, Quach V, Yu B, Jiang D, et al. Magnetic targeting of nanotheranostics enhances cerenkov radiation-induced photodynamic therapy. J Am Chem Soc. 2018;140(44):14971-14979.

[DOI] [PubMed] [PMC]
35. Peng W, Zhou T, Hu L, Vankann V, Bohn T, Bopp T, et al. Autonomous activation of a gated chemiluminescent photosensitizer enables targeted photodynamic therapy in tumor cells. J Am Chem Soc. 2025;147(31):27822-27834.

[DOI] [PubMed] [PMC]
36. Wang W, Ye B, Liu Y, Li Z, Huang Q, Zhou J, et al. A long-term self-driven metronomic photodynamic system for cancer therapy. Nat Commun. 2025;16(1):8823.

[DOI] [PubMed] [PMC]
37. Qiu ZW, Zhong YT, Lu ZM, Yan N, Kong RJ, Huang JQ, et al. Breaking physical barrier of fibrotic breast cancer for photodynamic immunotherapy by remodeling tumor extracellular matrix and reprogramming cancer-associated fibroblasts. ACS Nano. 2024;18(13):9713-9735.

[DOI] [PubMed]
38. DeNardo DG, Ruffell B. Macrophages as regulators of tumour immunity and immunotherapy. Nat Rev Immunol. 2019;19(6):369-382.

[DOI]
39. Veglia F, Sanseviero E, Gabrilovich DI. Myeloid-derived suppressor cells in the era of increasing myeloid cell diversity. Nat Rev Immunol. 2021;21(8):485-498.

[DOI] [PubMed] [PMC]
40. Christofides A, Strauss L, Yeo A, Cao C, Charest A, Boussiotis VA. The complex role of tumor-infiltrating macrophages. Nat Immunol. 2022;23(8):1148-1156.

[DOI] [PubMed] [PMC]
41. Pittet MJ, Michielin O, Migliorini D. Clinical relevance of tumour-associated macrophages. Nat Rev Clin Oncol. 2022;19(6):402-421.

[DOI] [PubMed]
42. Kumagai S, Togashi Y, Kamada T, Sugiyama E, Nishinakamura H, Takeuchi Y, et al. The PD-1 expression balance between effector and regulatory T cells predicts the clinical efficacy of PD-1 blockade therapies. Nat Immunol. 2020;21(11):1346-1358.

[DOI] [PubMed]
43. Li K, Shi H, Zhang B, Ou X, Ma Q, Chen Y, et al. Myeloid-derived suppressor cells as immunosuppressive regulators and therapeutic targets in cancer. Sig Transduct Target Ther. 2021;6:362.

[DOI]
44. Qu H, Li L, Chen H, Tang M, Cheng W, Lin TY, et al. Drug-drug conjugates self-assembled nanomedicines triggered photo-/immuno- therapy for synergistic cancer treatments. J Control Release. 2023;363:361-375.

[DOI] [PubMed] [PMC]
45. Zhao B, Chen X, Xu S, Xing Y, Shao J, Xiao Y, et al. On-demand ER stress modulation in tumor cells and TAMs via an adaptively transformable nanoplatform enhances photodynamic immunotherapy. Adv Mater. 2025;37(42):e07299.

[DOI] [PubMed]
46. Chang D, Yang J, Li Y, Min S, Ma Y, Xu T, et al. Spatiotemporally controlled nanomicelles for synergistic phototherapy and immune reprogramming in triple-negative breast cancer. ACS Nano. 2025;19(41):36323-36341.

[DOI] [PubMed]
47. Shanmugam M, Chiang CS, Hwang KC. 2240 nm NIR-IV photodynamic therapy can reverse ineffective anti-OX40 cancer immunotherapy to become effective. ACS Nano. 2025;19(41):36129-36147.

[DOI]
48. Chen D, Wang B, Li C, Tao H, Lu F, Ruan Z, et al. Ce6 derivative photodynamic therapy triggers PANoptosis and enhances antitumor immunity with LAG3 blockade in cutaneous squamous cell carcinoma. Cell Rep Med. 2025;6(7):102239.

[DOI] [PubMed] [PMC]
49. Liu S, Yang Z, Wang B, Huan S, Li Z, Wei X, et al. PD-L1-targeted photodynamic therapy orchestrates checkpoint blockade and immunogenic cell death for synergistic cancer immunotherapy. Redox Biol. 2026;91:104075.

[DOI] [PubMed] [PMC]
50. Xue X, Qu H, Bo R, Zhang D, Zhu Z, Xiang B, et al. A transformable nanoplatform with multiple therapeutic and immunostimulatory properties for treatment of advanced cancers. Biomaterials. 2023;299:122145.

[DOI] [PubMed]
51. Wang F, Xu W, Liu Y, Zhu S, Liu W, Bo S, et al. Spatiotemporally controlled tumor photodynamic/immunotherapy therapy based on upconversion hybrid nanosystem. Adv Sci. 2026;13(7):e15052.

[DOI] [PubMed] [PMC]
52. Xiao H, Li X, Li B, Yang S, Qin J, Han S, et al. Nanodrug inducing autophagy inhibition and mitochondria dysfunction for potentiating tumor photo-immunotherapy. Small. 2023;19(30):e2300280.

[DOI] [PubMed]
53. Liu Z, Liu X, Ma J, Zhang Y, Ye M, Liu H, et al. Harnessing targeted photodynamic therapy to synergistically activate T cell and NK cell responses in multiple myeloma. Adv Mater. 2026;38(18):e18663.

[DOI] [PubMed]
54. Chen H, Qu H, Pan Y, Cheng W, Xue X. Manganese-coordinated nanoparticle with high drug-loading capacity and synergistic photo-/immuno-therapy for cancer treatments. Biomaterials. 2025;312:122745.

[DOI] [PubMed]
55. Kroemer G, Galluzzi L, Kepp O, Zitvogel L. Immunogenic cell death in cancer therapy. Annu Rev Immunol. 2013;31:51-72.

[DOI] [PubMed]
56. Alzeibak R, Mishchenko TA, Shilyagina NY, Balalaeva IV, Vedunova MV, Krysko DV. Targeting immunogenic cancer cell death by photodynamic therapy: Past, present and future. J Immunother Cancer. 2021;9(1):e001926.

[DOI] [PubMed] [PMC]
57. Ding Q, Chen S, Hua S, Yoo J, Yoon C, Li Z, et al. Photoactivated nanovaccines. Chem Soc Rev. 2025;54(21):9807-9848.

[DOI]
58. Cai Y, Chai T, Nguyen W, Liu J, Xiao E, Ran X, et al. Phototherapy in cancer treatment: Strategies and challenges. Sig Transduct Target Ther. 2025;10:115.

[DOI]
59. Margulis V, Kaufman RP, Marcq G, Shvero A, Shore ND, Psutka SP, et al. ENLIGHTED phase 3 study: Interim results of efficacy and safety of padeliporfin vascular targeted photodynamic therapy (VTP) in the treatment of low-grade upper tract urothelial cancer (LG UTUC). J Clin Oncol. 2025;43(17):LBA4513.

[DOI]
60. Chen F, Hillemanns P, Ruan H, Chen X, Wang Y, Novak Z, et al. Photodynamic therapy for high-grade squamous intraepithelial lesions: A randomized controlled trial. Med. 2025;6(12):100851.

[DOI] [PubMed]
61. Cheng W, Yang J, Pan Y, Qu H, Duan Z, Wu J, et al. Noninvasive activation of local and systemic immunity with a sequential-targeting sonodynamic nanovaccine to treat glioblastoma. ACS Nano. 2025;19(30):27804-27824.

[DOI] [PubMed]
62. Yang M, Wang X, Peng M, Wang F, Hou S, Xing R, et al. Nanomaterials enhanced sonodynamic therapy for multiple tumor treatment. Nano-Micro Lett. 2025;17(1):157.

[DOI] [PubMed] [PMC]

Copyright

© The Author(s) 2026. This is an Open Access article licensed under a Creative Commons Attribution 4.0 International License (https://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, sharing, adaptation, distribution and reproduction in any medium or format, for any purpose, even commercially, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.

Publisher’s Note

Science Exploration remains a neutral stance on jurisdictional claims in published maps and institutional affiliations. The views expressed in this article are solely those of the author(s) and do not reflect the opinions of the Editors or the publisher.

Share And Cite

Science Exploration Style

Pan Y, Xue X. Overcoming three-layered tumor microenvironmental barriers to photodynamic therapy-induced systemic antitumor immunity. BME Horiz. 2026;4:202624. https://doi.org/10.70401/bmeh.2026.0032