Integrin-Targeted, Activatable Nanophototherapeutics for Immune Modulation: Enhancing Photoimmunotherapy Efficacy in Prostate Cancer Through Macrophage Reprogramming

Abstract

Prostate cancer is an epithelial malignancy with a high incidence among elderly men. Photochemistry-based dye photodrugs (known as photosensitizers) offer a promising clinical approach for treating tumors. These agents work by inducing immunogenic cell death (ICD), which activates antitumor immune response. This approach is favored owing to its minimal invasiveness, low toxicity, and high efficiency. However, the immunosuppressive microenvironment of characteristics of “cold” tumors significantly restricts the clinical efficacy of photodrugs. Developing an advanced nanocarrier system to deliver photodrugs and immune agonists for efficient drug delivery to tumor lesion sites and to reshape the immunosuppressive microenvironment is crucial in clinical practice. Therefore, in this study, we designed an integrin-targeted, activatable nano photodrug co-assembly with an immune agonist (RPST@IMQ) for enhancing photoimmunotherapy in prostate cancer via the reprogramming of tumor-associated macrophages. The active-targeted nanosystem enhanced the dosage of photodrug at the lesion site through systemic administration. High doses of glutathione at the tumor site cleaved the disulfide bonds of RPST@IMQ, releasing the photodrug and the immune agonist imiquimod (IMQ). Under photoirradiation, the photodrug generated significant doses of singlet oxygen to eliminate tumor cells, thereby inducing ICD to activate antitumor immune responses. Simultaneously, the released IMQ reprograms immunosuppressive M2-type tumor-associated macrophages (TAMs) in the tumor microenvironment into M1-type TAMs with tumor-killing capabilities, thereby converting “cold” tumors into “hot” tumors. This conversion enhances the therapeutic efficacy against primary and distant tumors in vivo. This study offers new insights into the development of innovative, smart, activatable nano photodrugs to enhance anticancer therapeutic outcomes.

Keywords

fluorescent dyes / imiquimod / photodynamic therapy / photoimmunotherapy / tumor-associated macrophages

References

[1] C. Cheng, J. Wang, P. Xu, et al., “Gremlin1 is a Therapeutically Targetable FGFR1 Ligand that Regulates Lineage Plasticity and Castration Resistance in Prostate Cancer,” Nature Cancer 3 (2022): 565.

[2] A. Jemal, M. M. Center, C. DeSantis, and E. M. Ward, “Global Patterns of Cancer Incidence and Mortality Rates and Trends,” Cancer Epidemiology and Prevention Biomarkers 19 (2010): 1893.

[3] H. Wang, Z. He, X.-A. Liu, et al., “Advances in Prostate-Specific Membrane Antigen (PSMA)-Targeted Phototheranostics of Prostate Cancer,” Small Structures 3 (2022): 2200036.

[4] Y. H. W. Derks, M. G. M. Schilham, M. Rijpkema, et al., “Imaging and Photodynamic Therapy of Prostate Cancer Using a Theranostic PSMA-Targeting Ligand,” European Journal of Nuclear Medicine and Molecular Imaging 50 (2023): 2872.

[5] B. Cioni, A. Zaalberg, J. R. van Beijnum, et al., “Androgen Receptor Signalling in Macrophages Promotes TREM-1-mediated Prostate Cancer Cell Line Migration and Invasion,” Nature Communications 11 (2020): 4498.

[6] S. Zeng, J. Wang, H. Kang, H. Li, X. Peng, and J. Yoon, “Photon-Driven Dye Induction Pyroptosis: An Emerging Anti-Tumor Immunotherapy Paradigm,” Angewandte Chemie International Edition 64 (2025): e202417899.

[7] H. Li, Y. Lu, J. Chung, et al., “Activation of Apoptosis by Rationally Constructing NIR Amphiphilic AIEgens: Surmounting the Shackle of Mitochondrial Membrane Potential for Amplified Tumor Ablation,” Chemical Science 12 (2021): 10522.

[8] M. Yang, C. Zhang, R. Wang, X. Wu, H. Li, and J. Yoon, “Cancer Immunotherapy Elicited by Immunogenic Cell Death Based on Smart Nanomaterials,” Small Methods 7 (2023): 2201381.

[9] J. Ding, Y. Lu, X. Zhao, et al., “Activating Iterative Revolutions of the Cancer-Immunity Cycle in Hypoxic Tumors With a Smart Nano-Regulator,” Advanced Materials 36 (2024): 2400196.

[10] Y. Wang, G. Li, J. Su, et al., “Spatiotemporal Controllable Sono-Nanovaccines Driven by Free-Field Based Whole-Body Ultrasound for Personalized Cancer Therapy,” Advancement of Science 11 (2024): 2307920.

[11] Y. Liu, Y. Liu, D. Xu, et al., “Targeting the Negative Feedback of Adenosine-A2AR Metabolic Pathway by a Tailored Nanoinhibitor for Photothermal Immunotherapy,” Advancement of Science 9 (2022): 2104182.

[12] Á.-P. Hernández, P. Juanes-Velasco, A. Landeira-Viñuela, et al., “Restoring the Immunity in the Tumor Microenvironment: Insights into Immunogenic Cell Death in Onco-Therapies,” Cancers 13 (2021): 2821.

[13] X. Xu, M. Chen, S. Jiang, Z. Pan, and C. Zhao, “Endoplasmic Reticulum-Targeting Iridium(III) Nanosonosensitizer Amplifies Immunogenic Cell Death for Boosted Tumor Sono-Immunotherapy,” Advanced Functional Materials 34 (2024): 2314780.

[14] N. P. Restifo, M. J. Smyth, and A. Snyder, “Acquired Resistance to Immunotherapy and Future Challenges,” Nature Reviews Cancer 16 (2016): 121.

[15] A. P. Castano, P. Mroz, and M. R. Hamblin, “Photodynamic Therapy and Anti-Tumour Immunity,” Nature Reviews Cancer 6 (2006): 535.

[16] N. Gong, M.-G. Alameh, R. El-Mayta, L. Xue, D. Weissman, and M. J. Mitchell, “Enhancing in Situ Cancer Vaccines Using Delivery Technologies,” Nature Review Drug Discovery 23 (2024): 607.

[17] Y.-Y. Zhao, X. Zhang, Z. Chen, et al., “Supramolecular Phthalocyanine Assemblies-Enhanced Synergistic Photodynamic and Photothermal Therapy Guided by Photoacoustic Imaging,” Aggregate 5 (2024): e514.

[18] Z. Zhuang, J. Li, P. Shen, Z. Zhao, and B. Z. Tang, “Exploring and Leveraging Aggregation Effects on Reactive Oxygen Species Generation in Photodynamic Therapy,” Aggregate 5 (2024): e540.

[19] Z. Li, Y. Zhang, M. Li, and J. Li, “Two-Step Targeting-Tunable Semiconducting Nanoswitches Amplify Mitochondrion Damage and PD-L1 Blockade for Orthotopic Pancreatic Cancer Therapy,” Advanced Functional Materials 35 (2025): 2413233.

[20] B. Li, W. Wang, L. Zhao, et al., “Aggregation-Induced Emission-Based Macrophage-Like Nanoparticles for Targeted Photothermal Therapy and Virus Transmission Blockage in Monkeypox,” Advanced Materials 36 (2024): 2305378.

[21] L. Wang, Y. He, T. He, et al., “Lymph Node-Targeted Immune-Activation Mediated by Imiquimod-Loaded Mesoporous Polydopamine Based-Nanocarriers,” Biomaterials 255 (2020): 120208.

[22] C. B. Rodell, S. P. Arlauckas, M. F. Cuccarese, et al., “TLR7/8-Agonist-Loaded Nanoparticles Promote the Polarization of Tumour-Associated Macrophages to Enhance Cancer Immunotherapy,” Nature Biomedical Engineering 2 (2018): 578.

[23] J. Wan, X. Zhang, D. Tang, T. Liu, and H. Xiao, “Biodegradable NIR-II Pseudo Conjugate Polymeric Nanoparticles Amplify Photodynamic Immunotherapy via Alleviation of Tumor Hypoxia and Tumor-Associated Macrophage Reprogramming,” Advanced Materials 35 (2023): 2209799.

[24] J. Jiang, J. Mei, S. Yi, et al., “Tumor Associated Macrophage and Microbe: The Potential Targets of Tumor Vaccine Delivery,” Advanced Drug Delivery Reviews 180 (2022): 114046.

[25] S. Di Somma, F. Napolitano, G. Portella, and A. M. Malfitano, “Cross Talk of Macrophages with Tumor Microenvironment Cells and Modulation of Macrophages in Cancer by Virotherapy,” Biomedicines 9 (2021): 1309.

[26] S. R. Gordon, R. L. Maute, B. W. Dulken, et al., “PD-1 Expression by Tumour-Associated Macrophages Inhibits Phagocytosis and Tumour Immunity,” Nature 545 (2017): 495.

[27] Q. Shi, Q. Shen, Y. Liu, et al., “Increased Glucose Metabolism in TAMs Fuels O-GlcNAcylation of Lysosomal Cathepsin B to Promote Cancer Metastasis and Chemoresistance,” Cancer Cell 40 (2022): 1207.

[28] M. J. Pittet, O. Michielin, and D. Migliorini, “Clinical Relevance of Tumour-associated Macrophages,” Nature reviews Clinical oncology 19 (2022): 402.

[29] S.-L. Li, H.-Y. Hou, X. Chu, et al., “Nanomaterials-Involved Tumor-Associated Macrophages Reprogramming for Antitumor Therapy,” ACS Nano 18 (2024): 7769.

[30] H. Hamidi and J. Ivaska, “Every Step of the Way: Integrins in Cancer Progression and Metastasis,” Nature Reviews Cancer 18 (2018): 533.

[31] E. Madrazo, A. C. Conde, and J. Redondo-Muñoz, “Inside the Cell: Integrins as New Governors of Nuclear Alterations?,” Cancers 9 (2017): 82.

[32] F. Wang, L. Chen, R. Zhang, Z. Chen, and L. Zhu, “RGD Peptide Conjugated Liposomal Drug Delivery System for Enhance Therapeutic Efficacy in Treating Bone Metastasis from Prostate Cancer,” Journal of Controlled Release 196 (2014): 222.

[33] A. Sheikh, S. Md, and P. Kesharwani, “RGD Engineered Dendrimer Nanotherapeutic as an Emerging Targeted Approach in Cancer Therapy,” Journal of Controlled Release 340 (2021): 221.

[34] Y. Hao, H. Li, X. Ge, et al., “Tumor-Selective Activation of Toll-Like Receptor 7/8 Agonist Nano-Immunomodulator Generates Safe Anti-Tumor Immune Responses Upon Systemic Administration,” Angewandte Chemie International Edition 61 (2022): e202214992.

[35] K. Ni, T. Luo, A. Culbert, M. Kaufmann, X. Jiang, and W. Lin, “Nanoscale Metal-Organic Framework Co-Delivers TLR-7 Agonists and Anti-CD47 Antibodies to Modulate Macrophages and Orchestrate Cancer Immunotherapy,” Journal of American Chemical Society 142 (2020): 12579.

[36] H. Cui, L. Zhang, S. Zeng, et al., “Charge-Reversible Pro-Ribonuclease Enveloped in Virus-Like Synthetic Nanocapsules for Systemic Treatment of Intractable Glioma,” ACS Applied Materials & Interfaces 14 (2022): 30493.

[37] Y. Yang and W. Sun, “Recent Advances in Redox-Responsive Nanoparticles for Combined Cancer Therapy,” Nanoscale Advances 4 (2022): 3504.

[38] H. Li, J. Wang, H. Kim, X. Peng, and J. Yoon, “Activatable Near-Infrared Versatile Fluorescent and Chemiluminescent Dyes Based on the Dicyanomethylene-4 H-Pyran Scaffold: From Design to Imaging and Theranostics,” Angewandte Chemie International Edition 63 (2024): e202311764.

[39] N. Ghorbani, R. Yaghubi, J. Davoodi, and S. Pahlavan, “How Does Caspases Regulation Play Role in Cell Decisions? Apoptosis and Beyond,” Molecular and Cellular Biochemistry 479 (2024): 1599.

[40] M. Przygoda, D. Bartusik-Aebisher, K. Dynarowicz, G. Cieślar, A. Kawczyk-Krupka, and D. Aebisher, “Cellular Mechanisms of Singlet Oxygen in Photodynamic Therapy,” International Journal of Molecular Sciences 24 (2023): 16890.

[41] S. Li, S. Jiang, M. S. U. Rahman, et al., “Pre-Induced ICD Membrane-Coated Carrier-Free Nanoparticles for the Personalized Lung Cancer Immunotherapy,” Small Methods 7 (2023): 2201569.

[42] H. Cui, M. Zhang, L. Zhang, et al., “pH-responsive Organic/Inorganic Hybrid Nanocolloids for Transcellular Delivery of Ribonucleolytic Payloads Toward Targeted Anti-Glioma Therapy,” Journal of Colloid & Interface Science 634 (2023): 388.

[43] T. Yang, Y. Mochida, X. Liu, et al., “Conjugation of Glucosylated Polymer Chains to Checkpoint Blockade Antibodies Augments Their Efficacy and Specificity for Glioblastoma,” Nature Biomedical Engineering 5 (2021): 1274.

[44] H. Gu, W. Sun, J. Du, J. Fan, and X. Peng, “Dual-Acceptor Engineering of Donor-Acceptor Type Molecules for All-Round Boosting Anti-Tumor Phototherapy,” Smart Molecules 2 (2024): e20230014.

[45] L. Yin, X. Li, R. Wang, Y. Zeng, Z. Zeng, and T. Xie, “Recent Research Progress of RGD Peptide-Modified Nanodrug Delivery Systems in Tumor Therapy,” International Journal of Peptide Research and Therapeutics 29 (2023): 53.

[46] L. Tiberio, A. Del Prete, T. Schioppa, F. Sozio, D. Bosisio, and S. Sozzani, “Chemokine and Chemotactic Signals in Dendritic Cell Migration,” Cellular Molecular Immunology 15 (2018): 346.

[47] M. Cao, H. Yan, X. Han, et al., “Ginseng-Derived Nanoparticles Alter Macrophage Polarization to Inhibit Melanoma Growth,” Journal for ImmunoTherapy of Cancer 7 (2019): 326.

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